Order Code RL32909
CRS Report for Congress
Received through the CRS Web
Federal Protection for Human Research Subjects:
An Analysis of the Common Rule
and Its Interactions with FDA Regulations
and the HIPAA Privacy Rule
Updated July 19, 2005
Erin D. Williams
Specialist in Bioethical Policy
Domestic Social Policy Division
Congressional Research Service ˜ The Library of Congress
Federal Protection for Human Research Subjects: An
Analysis of the Common Rule and Its Interactions with
FDA Regulations and the HIPAA Privacy Rule
The Common Rule governs research that is conducted on human beings if it is
funded by one of 19 federal agencies. It requires a review of proposed research by
an Institutional Review Board (IRB), the informed consent of research subjects, and
institutional assurances of compliance with the regulations.
In 1974, 45 CFR 46 was published following some cases of harm to human
subjects, such as those caused by thalidomide drug trials and the United States Public
Health Service syphilis study in Tuskeegee, Alabama. The regulations had their roots
in numerous international agreements, such as the Nuremberg Code and the
Declaration of Helsinki, and domestic policies, such as those put forth by the
Department of Health, Education and Welfare (DHEW; now the Department of
Health and Human Services, HHS). In 1991, 16 federal agencies adopted the terms
of 45 CFR 46, Subpart A, thus creating the Common Rule.
Since the Common Rule took effect, events like the death of Jesse Gelsinger in
1999 due to his participation a clinical trial have prompted scrutiny of the Rule and
its ability to protect research subjects. In order to help enhance research subject
protections, in 2000 HHS removed the Office for Protection from Research Risks
(OPRR) from the National Institutes of Health (NIH), and created a new office — the
Office for Human Research Protections (OHRP) — in an elevated position in HHS.
In addition, groups like the National Bioethics Advisory Commission and the
National Academies raised the following policy questions: (1) Should the Common
Rule be applied to non-federally funded research, social and behavioral research,
international clinical trials, and research with human biological materials? (2) Do
existing provisions ensure the participation and protection of children, prisoners,
minorities, those with diminished capacity, pregnant women, fetuses, neonates, and
people in emergency situations? (3) What should be the requirements regarding
IRBs’ membership, responsibilities, training, and registration? (4) How should
conflicts of interest, accreditation, ongoing research, and adverse event reporting be
handled? (5) How should basic and research-related medical care’s cost, and IRB
liability for harm be handled? (6) How should the human subjects protection system
be reassessed, adequate resources ensured, and the burdens and benefits of amending
regulations appropriately weighed? (7) How does 45 CFR 46 interact with the Food
and Drug Administration (FDA) regulations for the protection of human subjects (21
CFR 50 and 56), and the Privacy Rule of the Health Insurance Portability and
Accountability Act of 1996 (HIPAA) (45 CFR 146)?
Legislation to revise the Common Rule has been introduced in every Congress
since 1997. In the 109th, the PhRMA Act of 2005 (H.R. 870) was introduced, to
provide criminal penalties for concealing evidence of serious drug adverse events.
Bills introduced in former Congresses include the Protection for Participants in
Research Act of 2003 (H.R. 3594, 108th Congress), the Research Revitalization Act
of 2002 (S. 3060, 107th Congress), and the Human Research Subject Protections Act
of 2002 (H.R. 4697, 107th Congress). This report will be updated as needed.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Informed Consent . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Assurance of Compliance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
The Common Rule and 45 CFR 46 . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
Other Federal Regulations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
Concerns About the Common Rule . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
Proposed Legislation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
Report Contents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
History of the Common Rule and Current Regulations . . . . . . . . . . . . . . . . . . . . 12
Issues, Recommendations, and Proposed Legislation . . . . . . . . . . . . . . . . . . . . . 17
Scope of the Common Rule . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
Non-Federally Funded Research and Federally Funded Research
Outside the Scope of the Common Rule . . . . . . . . . . . . . . . . . . . 18
Clinical Trials in Developing Nations . . . . . . . . . . . . . . . . . . . . . . . . . 20
Human Biological Materials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
Social and Behavioral Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
Proposed Legislation affecting the Scope of the Common Rule . . . . . 25
Inclusion and Protection of Vulnerable Populations . . . . . . . . . . . . . . . . . . 26
Minorities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
Children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
Children who are Wards . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
Prisoners . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
Pregnant Women, Human Fetuses, and Neonates . . . . . . . . . . . . . . . . 33
Diminished Capacity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
Proposed Legislation Affecting the Inclusion and Protection of
Vulnerable Populations in Research . . . . . . . . . . . . . . . . . . . . . . 35
Institutional Review Boards (IRBs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
IRB Membership . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
IRB Duties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
IRB Registration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
Defining and Weighing Risks and Potential Benefits . . . . . . . . . . . . . 39
IRB Shopping . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
Proposed Legislation Affecting IRBs . . . . . . . . . . . . . . . . . . . . . . . . . 43
Mistakes and Misconduct . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
Conflicts of Interest Rules . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
Accreditation of IRBs, Researchers and Institutions . . . . . . . . . . . . . . 46
Adverse Event Reporting and Multisite Research . . . . . . . . . . . . . . . . 49
Informed Consent . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
Monitoring of Ongoing Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
Proposed Legislation Affecting the Prevention of Mistakes
and Misconduct . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54
Injuries and Medical Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
Cost of Medical Care During Human Subjects Research
and Compensation for Research-Related Injuries . . . . . . . . . . . . 56
IRB Liability for Research-Related Injury . . . . . . . . . . . . . . . . . . . . . . 57
The Future of Human Subjects Research Protections . . . . . . . . . . . . . . . . . 58
Periodic Reassessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58
Additional Resources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
Regulatory Change . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
Proposed Legislation Affecting Future Human Subjects
Protections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60
Appendix A: The Common Rule’s (and 45 CFR 46’s) Interaction with
FDA Regulations and the HIPAA Privacy Rule . . . . . . . . . . . . . . . . . . . . . 61
The HIPAA Privacy Rule . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61
Food and Drug Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64
Proposed Legislation Related to Harmonization . . . . . . . . . . . . . . . . . 67
Appendix B. History and Requirements of the Common Rule . . . . . . . . . . . . . . 68
International Codes and Declarations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68
Hippocratic Oath: Doctor Knows Best . . . . . . . . . . . . . . . . . . . . . . . . 68
Nuremberg Code: Subject’s Choice . . . . . . . . . . . . . . . . . . . . . . . . . . . 68
Declaration of Helsinki: Physicians Sign On . . . . . . . . . . . . . . . . . . . 69
United States Regulations Before the Common Rule . . . . . . . . . . . . . . . . . 70
NIH Clinical Center Policy of 1953 . . . . . . . . . . . . . . . . . . . . . . . . . . . 70
Drug Amendments of 1962 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70
Events Leading Up to the Common Rule . . . . . . . . . . . . . . . . . . . . . . . . . . 71
Reports of Unethical Practices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72
1966 Surgeon General’s Policy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72
1971 DHEW Guide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
The Tuskegee Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
DHEW and Congress Take Action . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
45 CFR 46, Subpart A: The Basis of the Common Rule . . . . . . . . . . . . . . 74
Basic Requirements of the Common Rule . . . . . . . . . . . . . . . . . . . . . . 75
List of Tables
Table 1. Key Human Subjects Protection Reports, 1995-2004 . . . . . . . . . . . . . . 17
Federal Protection for Human Research
Subjects: An Analysis of the Common Rule
and Its Interactions with FDA Regulations
and the HIPAA Privacy Rule
Congress has shown a keen interest in the Common Rule largely because of the
federal government’s longstanding investment in medical research, and its interest
in research-subject safety. The Common Rule (45 CFR 46, Subpart A)1 is a set of
regulations that govern most federally funded research conducted on human beings.
Its three basic requirements are aimed at protecting research subjects: the informed
consent of research subjects, a review of proposed research by an Institutional
Review Board (IRB), and institutional assurances of compliance with the regulations.
Informed Consent. Meaningful informed consent is one cornerstone of
human subjects protections. To provide informed consent, a potential research
subject must both understand what participation in a study entails (in other words, be
informed), and agree to participate (consent). The Common Rule requires that a
researcher obtain informed consent (usually in writing) from a living person or their
legally authorized representative before the person can be admitted to a study.
The Common Rule’s informed consent regulations focus primarily on the
elements and documentation of informed consent rather than on the process used to
obtain it. As to the process, the regulations require that informed consent be sought
only under circumstances that provide the prospective subject sufficient opportunity
to consider whether or not to participate, and that minimize the possibility of
coercion or undue influence. Regarding the content and documentation, the
Common Rule requires that information be given in language understandable to the
subject, and that informed consent be clear of any exculpatory language releasing the
investigator, the sponsor, the institution or its agents from liability for negligence (45
CFR 46.116). In addition, the Common Rule specifies that all of the following
elements must be provided when informed consent is sought (45 CFR 46.116(a)):
The term the Common Rule refers to federal regulations for the protection of human
research participants that have been adopted by various federal agencies in their respective
sections of the Code of Federal Regulations (CFR). When provisions of the Common Rule
are cited in this report, readers are directed to the HHS regulations that served as the basis
for the Common Rule (45 CFR 46, Subpart A) so that they may easily locate the text.
a statement that the study involves research, an explanation of the
purposes of the research and the expected duration of the subject’s
participation, a description of the procedures to be followed, and
identification of any procedures which are experimental;
a description of any reasonably foreseeable risks or discomforts to
a description of any benefits to the subject or to others which may
reasonably be expected from the research;
a disclosure of appropriate alternative procedures or courses of
treatment, if any, that might be advantageous to the subject;
a statement describing the extent, if any, to which confidentiality of
records identifying the subject will be maintained;
for research involving more than minimal risk, an explanation as to
whether any compensation and an explanation as to whether any
medical treatments are available if injury occurs and, if so, what they
consist of, or where further information may be obtained;
an explanation of whom to contact for answers to pertinent questions
about the research and research subjects’ rights, and whom to
contact in the event of a research-related injury to the subject; and
a statement that participation is voluntary, refusal to participate will
involve no penalty or loss of benefits to which the subject is
otherwise entitled, and the subject may discontinue participation at
any time without penalty or loss of benefits to which the subject is
When informed consent is sought, the Common Rule also requires other
information to be provided if applicable, such as any additional costs to the subject
that may result from participation in the research, or a statement that the particular
treatment or procedure may involve risks to the subject, which are currently
unforeseeable (45 CFR 46.116(b)).
IRB Review. The Common Rule’s primary mechanism for ensuring the
adequacy of informed consent and other aspects of human subjects protection is IRB
review. IRBs review and have authority to approve, require modifications in (to
secure approval), or disapprove all research activities covered by the Common Rule
(45 CFR 46.109(a)). The Common Rule requires that protocols for human subjects
research be IRB approved before the research can begin (45 CFR 46.103(b)). The
Common Rule does not require that IRBs be accredited,2 but it does require them to
meet certain membership and review procedures.
IRBs generally comprise volunteers who examine proposed and ongoing
scientific research to ensure that human subjects are properly protected. The
Common Rule (45 CFR 46.107) requires that each IRB have the following:
Accreditation is procedure by which an authoritative body gives formal recognition that
a body or person is competent to carry out specific tasks.
at least five members;
members with varying backgrounds to promote complete and
adequate review of research activities commonly conducted by the
members that are not entirely of one profession;
at least one member whose primary concerns are in scientific areas
and at least one member whose primary concerns are in nonscientific
at least one member who is not affiliated with the institution;
a membership diverse in race, gender, and cultural backgrounds, and
having sensitivity to community attitudes; and
if an IRB regularly reviews research that involves a vulnerable
category of subjects, such as children, prisoners, pregnant women,
or handicapped or mentally disabled persons, consideration shall be
given to the inclusion of one or more individuals who are
knowledgeable about and experienced in working with these
IRBs are to meet as necessary (in institutions with a high volume of protocols,
this is often monthly or more frequently; in smaller-volume institutions it is often
less frequently), to conduct their reviews. Reviews may be conducted only at
convened meetings at which a majority of the members of the IRB are present,
including at least one member whose primary concerns are in nonscientific areas. In
order for the research to be approved, it must receive the approval of a majority of
those members present at the meeting (45 CFR 46.108(b)). IRBs are to conduct initial
reviews of proposed research, and also monitor ongoing research, re-reviewing it at
least once per year (45 CFR 46.109(e)). No IRB may have a member participate in
the IRB’s initial or continuing review of any project in which the member has a
conflicting interest, except to provide information requested by the IRB (45 CFR
46.107(e)). To facilitate this monitoring and reevaluation, IRBs are to be provided
with reports of unanticipated problems involving risks to subjects (or others) that
arise during research,3 and to reevaluate the human subjects protections in the
protocol if necessary (45 CFR 46.103(b)(5)).
The Common Rule does not specify which procedures an IRB must follow in
its review of protocols — leaving that to local control — but it does require that there
be written procedures. The procedures must specify how an IRB will conduct its
initial and continuing reviews of research, report its findings and actions to the
investigator and the institution, and determine which projects require review more
often than annually and which need verification from sources other than the
investigators that no material changes have occurred since previous IRB review. In
addition, there must be written procedures that ensure prompt reporting to the IRB
of unanticipated problems, noncompliance, and proposed changes in research
activities (45 CFR 46.103(b)(4)-(5)).
Some unanticipated problems involving risks to subjects may be referred to as adverse
events (AEs), although the term is not used in the Common Rule itself.
The Common Rule requires that an IRB determine that all of the following
requirements are satisfied in order to approve proposed research (45 CFR 46.111):
informed consent is sought from each subject according to the
requirements described above;
risks to subjects are minimized;
risks to subjects are reasonable in relation to anticipated benefits, if
any, to subjects, and the importance of the knowledge that may
reasonably be expected to result;
that the selection of subjects is equitable;
when appropriate, that the research plan makes adequate provision
for monitoring the data collected to ensure the safety of subjects;
when appropriate, that there are adequate provisions to protect the
privacy of subjects and to maintain the confidentiality of data; and
if some or all of the subjects are likely to be vulnerable to coercion
or undue influence, such as children, prisoners, pregnant women,
mentally disabled persons, or economically or educationally
disadvantaged persons, that the study has additional safeguards to
protect the rights and welfare of these subjects.
In evaluating risks and benefits, the IRB should consider only those risks and
benefits that may result from the research (as distinguished from risks and benefits
of therapies subjects would receive even if not participating in the research). The
IRB should not consider possible long-range effects of applying knowledge gained
in the research (for example, the possible effects of the research on public policy) as
among those research risks that fall within the purview of its responsibility (45 CFR
46.111(a)(2). The Common Rule leaves the weighing of risks and benefits in
individual protocols up to local IRBs, enabling them to apply local community
Not every research project involving human subjects is required to gain IRB
approval through the formal review process described above. Certain types of
research projects may qualify for expedited review. Expedited review may be carried
out by the IRB chairperson or by one or more experienced reviewers designated by
the chairperson from among members of the IRB. In reviewing the research, the
reviewers may exercise all of the authorities of the IRB except that the reviewers may
not disapprove the research. A research activity may be disapproved only after
review in accordance with the non-expedited procedure. The Common Rule allows
an IRB to use an expedited review procedure for one or both of the following: (1)
research that the HHS Secretary has determined to be eligible for expedited review4
and found by the reviewer(s) to involve no more than minimal risk; (2) minor
changes in previously approved research during the period (of one year or less) for
which approval is authorized.
A list of the HHS Secretary’s categories of research that qualify for expedited review is
available at [http://www.hhs.gov/ohrp/humansubjects/guidance/expedited98.htm], visited
Apr. 14, 2005.
The Common Rule defines minimal risk as that in which the probability and
magnitude of harm or discomfort anticipated in the research are not greater in and of
themselves than those ordinarily encountered in daily life or during the performance
of routine physical or psychological examinations or tests (45 CFR 46.102(i)).
Assurance of Compliance. The Common Rule’s primary mechanism for
ensuring that a research institution is complying with regulatory requirements for
IRBs and for other human research subject protections is through requiring
institutional assurances. An assurance is a written document containing promises
of regulatory compliance. To receive federal funding for research covered by the
Common Rule, each institution is required to provide an assurance of compliance
with the Common Rule to the head of the federal Department or Agency from which
it is receiving funding. As an alternative, the institution may substitute an assurance
provided to Office for Protection from Research Risks (OPRR, now the Office for
Human Research Protections: OHRP), if the assurance is current, approved for
federal-wide use by HHS, and applicable to the research in question. (45 CFR
To satisfy the Common Rule’s requirements, an assurance must certify that the
research has been reviewed, approved, and will be subject to continuing review by
an IRB (45 CFR 46.103(b)). The assurance must include, among other things:
designation of one or more IRBs established in accordance with the
requirements of the Rule, and for which provisions are made for
meeting space and sufficient staff to support the IRB’s review and
recordkeeping duties(45 CFR 46.103(b)(2)).
written IRB procedures for initial, continuing, and expedited review,
and for ensuring prompt reporting of certain unanticipated problems
(45 CFR 46.103(b)(4)-(5)).
a statement of principles governing the institution for protecting the
rights and welfare of human subjects of research conducted at or
sponsored by the institution, regardless of whether the research is
subject to federal regulation (45 CFR 46.103(b)(1).
a list of IRB members identified by name; earned degrees;
representative capacity; indications of experience such as board
certifications, licenses, etc., sufficient to describe each member’s
chief anticipated contributions to IRB deliberations; and any
employment or other relationship between each member and the
institution; for example: full-time employee, part-time employee,
member of governing panel or board, stockholder, paid or unpaid
consultant (45 CFR 46.103(b)(2)).
Through the assurance process, OHRP — which can approve assurances for
federal-wide use — may gather the above information about some IRBs.
The Common Rule and 45 CFR 46. The Department of Health and Human
Services (HHS) (formerly the Department of Health Education and Welfare —
DHEW - until 1980) was the first federal agency to publically develop formal
policies for the protection of human subjects.5 In 1974, after more than 20 years of
DHEW involvement and consideration, the regulations were codified: 45 CFR 46,
Subpart A. In 1991, the terms of Subpart A of 45 CFR 46 were adopted by 16 federal
agencies, thus creating the Common Rule.
Since 1974, HHS has promulgated and amended additional regulations to give
extra protections to certain groups of human subjects, including children, prisoners,
and pregnant women, as well as fetuses and human in vitro fertilization. These
regulations for the protection of vulnerable populations. 45 CFR 46 Subparts B, C,
and D provide protections for women and neonates, prisoners, and children,
respectively. These Subparts apply to HHS funded research, but are not a part of the
Common Rule. They do not generally apply to the other federal agencies that have
adopted the Common Rule, except for cases in which an agency has voluntarily
adopted one or more of the additional Subparts. In this report, 45 CFR 46 will refer
to the full regulation, including all Subparts. The Common Rule will refer only to
the terms of Subpart A.
Today the Common Rule governs 19 federal departments and agencies.6 The
Common Rule applies to research conducted at or funded by the agencies that have
adopted it, though it has not been adopted by all agencies that fund research.7 This
means that, in order to be eligible to receive funding from one of the agencies that
has adopted the Common Rule and/or other subsections of 45 CFR 46, researchers
and institutions must abide by the relevant regulatory provisions.8 It also means that
In 1953, Secretary of Defense Charles Wilson issued a top secret memorandum
establishing policy for research related to atomic, biological, and chemical warfare. The
policy incorporated the principles of the Nuremberg Code and two additional protections
— a prohibition on research involving prisoners of war and a requirement that the Secretary
of the appropriate military service approve research studies. National Bioethics Advisory
Commission, Ethical and Policy Issues in Research Involving Human Participants, Aug.
The Common Rule was developed as such by the Interagency Federal Coordinating
Council for Science, Engineering and Technology. The following departments and agencies
have adopted it: Department of Health and Human Services, Department of Agriculture,
Department of Energy, National Aeronautics and Space Administration, Department of
Defense, Consumer Product Safety Commission, International Development Cooperation
Agency (Agency for International Development), Department of Housing and Urban
Development, Department of Justice, Department of Defense, Department of Education,
Department of Veterans Affairs, Environmental Protection Agency, National Science
Foundation, and Department of Transportation. The Rule applies to the Central Intelligence
Agency (by Executive Order 12333), the Social Security Administration (by P.L. 103-296),
and the Department of Homeland Security (by P.L 108-458). The Office of Science and
Technology Policy signed but did not codify the Rule because it does not conduct clinical
For example, the Department of Labor and the Nuclear Regulatory Commission are
reported to sponsor human subjects research but have not adopted the Common Rule.
The Common Rule exempts some categories of research from its requirements, and gives
Department or Agency heads final judgment as to whether a particular activity is covered.
Examples of types of research that may qualify as exempt are those that involve the use of
federal law does not require research conducted without federal money (or with
money from an agency that has not adopted the Common Rule and/or 45 CFR 46) to
be conducted in accordance with these regulations. A number of private companies
have voluntarily chosen to follow the Common Rule, though these are not subject to
federal enforcement mechanisms if they fail to comply.
Some federal agencies and departments have adopted Subparts of 45 CFR 46
other than the Common Rule, or have implemented their own regulations governing
certain types of human subjects research. For example, the Department of Education
has adopted Subpart D, which provides additional protections for children involved
in research (35 CFR 97.401-409). The Department of Justice’s Bureau of Prisons has
adopted its own regulations regarding research involving prisoners, which are similar
to, though more rigorous than 45 CFR 46, Subpart C (28 CFR 512.10-21). The
Department of Veterans Affairs has an Office of Research Oversight, which is
responsible for advising the Under Secretary for Health on matters of compliance and
assurance in human subjects protections, research safety, and research impropriety
and misconduct (P.L. 108-170, § 401). In addition, the Veterans Administration has
engaged an external contractor to inspect and certify the human subjects protection
program of every VA facility conducting research involving human subjects.9
Other Federal Regulations. The Common Rule and 45 CFR 46 are not the
only federal regulations that may provide protections for human subjects. One
additional set of federal regulations for the protection of human subjects has been put
forth by the Food and Drug Administration (FDA). FDA is the federal agency
responsible for reviewing the safety and efficacy of new biomedical products (drugs,
devices, vaccines, etc.) before they can be marketed in the United States. FDA’s
regulations for the protection of human subjects (21 CFR 50, 56) are very similar to
— and in many instances identical to — the Common Rule. They require informed
consent (21 CFR 50), IRB review (21 CFR 56), and assurance of IRB review (21
There are some key differences between FDA regulations, and the Common
Rule and 45 CFR 46. FDA regulations have a scope and set of definitions targeted
to clinical trials10 that evaluate products for marketing rather than to basic research.11
educational tests, demonstration projects conduced by Agency heads to assess public benefit
or service programs, and some others (45 CFR 46.101(b), (c)).
Testimony of Thomas L. Garthwaite, M.D., Under Secretary for Health, Department of
Veterans Affairs on the Protection of Human Subjects of Research in the Veterans Health
Administration before the Subcommittee on Oversight and Investigations of the Committee
on Veterans’ Affairs, U.S. House of Representatives (Sept. 28, 2000), at
[http://veterans.house.gov/hearings/schedule106/sept00/9-28-00/tgarthwa.htm], visited May
A clinical trial is one type of human subjects research in which a hypothesis is tested in
a randomized, controlled and usually blinded setting. “Randomized” means that the subjects
have been randomly divided into two or more groups; one or more group(s) receive an
intervention (such as a drug) and another (a control group) does not. “Controlled” means
The broadest difference is that, unlike the Common Rule, FDA’s regulations for the
protection of human research participants attach when research is used to support an
application to FDA for marketing, regardless of the funding source. Other subtler
distinctions, which have prompted public calls for harmonizing the two sets of
regulations include FDA’s regulatory provisions for emergency use of a product in
a critical situation, and requirements for investigators to disclose financial conflicts
of interest, whereas the Common Rule does not. In addition, 45 CFR 46 makes two
allowances that FDA regulations do not: for international research, 45 CFR 46,
Subpart A (the Common Rule), allows a department or agency head to approve the
substitution of foreign procedures in lieu of HHS policy; and for research involving
children, 45 CFR 46, Subpart D, stipulates that an IRB may waive the parental
consent requirement if necessary to protect the subjects.
A third set of federal regulations that may provide some protections for human
subjects is the Standards for Privacy of Individually Identifiable Health
Information,12 or Privacy Rule (45 CFR 164), which the HHS Secretary issued
pursuant to the Health Insurance Portability and Accountability Act of 1996.
(HIPAA, P.L.104-191) HIPAA’s stated purpose focused broadly upon health
insurance — improving portability and continuity of health insurance coverage, to
combating waste, fraud, and abuse in health insurance and health care delivery, to
simplifying the administration of health insurance, among other things. The Privacy
Rule regulates certain health-related entities’ (covered entities’)13 handling of
protected health information (PHI - which is, generally speaking, individually
identifiable health information). When human subjects research involves the
handling of PHI by a covered entity, the protections of the Privacy Rule attach,
regardless of the funding source, or whether the research will be used to support an
application to FDA for marketing.
The requirements of the Privacy Rule are somewhat different than those of the
Common Rule. Whereas the Common Rule requires informed consent before the
person can participate in research, the Privacy Rule requires a patient’s authorization
steps have been taken to minimize the effects of variables other than the intervention that
might affect the outcome (such as, for example, subjects’ age, health problems, etc.).
“Blinded” means that the subjects, and sometimes the researchers interacting with the
subjects and recording results, do not know which group the subjects are in. Human-subjects
research is a broader category than clinical trials, which would include non-clinical trials
such as surveys and observational studies.
Basic research is broadly defined as asking questions to obtain knowledge. It may
encompass laboratory, animal, or other study methods. It is a broader category than human
subjects research (which is basic research that involves human beings).
For more information, see CRS Report RS20500, Medical Records Privacy: Questions
and Answers on the HIPAA Final Rule, by C. Steven Redhead.
A covered entity is a health plan, health clearing house, or any health care provider who
transmits health information in electronic form in connection with transactions for which
the HHS Secretary has adopted standards under HIPAA (45 CFR 164.103).
for the release of his or her PHI (45 CFR 46.508).14 The elements of authorization
are focused on disclosure of information rather than on preparation for participation
in research. Elements include, for example, that authorization must be in plain
language, contain a description of the information and its proposed use(s), contain
the name of the person requesting authorization, list a start and end date for the
research, include the authorization’s expiration date, and state the individual’s right
to revoke his or her authorization.15
The Privacy Rule requires authorization for the release of PHI, in some cases
in which the Common Rule does not require informed consent, for example, for postmortem research (the Common Rule applies only to research involving living
persons).16 One other distinction is that, although the Privacy Rule allows
authorization to be combined with informed consent, it specifically prohibits the
combination of authorizations for various research projects (compound
authorization) (45 CFR 164.508(b)(3)). The Common Rule contains no equivalent
prohibition. Another distinction is that the Privacy Rule does not require oversight
for background research17 that is conducted without removing PHI from the covered
entity (45 CFR 164.512(i)(1)(ii)). Under the terms of the Common Rule, this type
of inquiry would constitute human subjects research and trigger regulatory provisions
(45 CFR 46.102(d)).
Another point of distinction between the Privacy Rule and the Common Rule
is that the Privacy Rule allows for certain actions to be taken by either an IRB or a
privacy board. The Common Rule requires action by an IRB. According to the
terms of the Privacy Rule, a privacy board, which may be an IRB (45 CFR
The Privacy Rule specifically permits authorization to be combined with informed consent
(45 CFR 164.508(b)(3)(i)). In addition, in some circumstances — including the conduct
of research — the Privacy Rule’s requirements may be satisfied by either informed consent
or authorization. See, e.g., 45 CFR 164.532(a). There are also certain exceptions to the
authorization requirement, which allow for standard health-provider and insurer business
practices, for the provision of health care, and for circumstances in which the requirement
has been waived by an IRB or privacy board (45 CFR 504-506).
For a full list of the required elements of authorization, see 45 CFR 164.508 (c).
45 CFR 164.502(f) (Privacy Rule); 45 CFR 46.102(f) (Common Rule). There are certain
exceptions to the Privacy Rule’s requirement regarding postmortem research at 45 CFR
Background research might entail reviewing patients’ medical files to determine the
frequency of a common intervention, so that the need for an improved intervention could
has members with varying backgrounds and appropriate professional
competency as necessary to review the effect of the research protocol
on the individual’s privacy rights and related interests;
includes at least one member who is not affiliated with the covered
entity, not affiliated with any entity conducting or sponsoring the
research, and not related to any person who is affiliated with any of
such entities; and
does not have any member participating in a review of any project
in which the member has a conflict of interest.
Because the Common Rule, 45 CFR 46, FDA regulations, and the Privacy Rule
all have different triggers, human subjects research may have to meet all, some, or
none of these federal requirements. For example, an HHS-funded study conducted
by a hospital to help test a drug for marketing would be subject to all of the
regulations. A privately-funded study conducted in a practitioner’s office to compare
surgical techniques may be subject to none of them.
Concerns About the Common Rule. Though the spectrum of regulations
that may govern human subjects research have been implemented over time, the
regulations that are the basis of the Common Rule were crafted over 30 years ago.
At that time, a research project was typically conducted at a single location, and was
largely federally funded. Since the original regulations took effect, the number of
privately funded and/or multi-center trials has increased. Events such as the 1999
death of Jesse Gelsinger due to his participation in a clinical trial have led some
policy makers to call for changes to the Common Rule.
Concerns about the Common Rule have been expressed in a number of areas:
The Rule does not apply to all federally funded or any nonfederally funded human subjects research; therefore, some
research may be conducted without federal oversight and
without protection for human subjects.
Vulnerable populations may not receive adequate protection
in research because Subparts B-D of 45 CFR 46, which are
designed to protect children, prisoners, pregnant women,
human fetuses, and neonates, have not been uniformly adopted
by agencies other than HHS; in addition, the Common Rule
does not contain provisions specific to research on minority
populations, or to research on those with diminished capacity
in emergency situations.
Some IRBs may have duties too broad and memberships too
narrow to ensure proper protections. In addition, variance in
different IRBs’ reviews may lead investigators to seek more
lenient IRBs, a process sometimes called “IRB shopping.”
Rules governing conflicts of interest, accreditation of
investigators, sponsors, and IRBs, adverse event reporting, and
monitoring of ongoing research may need more refinement to
Who should pay for routine and injury-related medical care
during research remains unresolved.
Mechanisms to easily refine the Common Rule are not in
Simultaneous application of the Common Rule, the Privacy
Rule, and/or FDA regulations have created confusing
requirements for some conducting human subjects research.
The related topic of the reporting and publication of clinical trials data and
results is beyond the scope of this report and is not discussed herein.18
HHS has the authority to address some of the above issues by amending the
Common Rule, though it does not have the authority to apply the Common Rule or
45 CFR 46 to research conducted without federal funding. In addition, HHS does not
have the authority to regulate its sister agencies, so each agency that has adopted
Common Rule (and each company that now voluntarily follows the Rule) would have
to make an independent decision to adopt and implement amendments made by HHS.
Therefore, groups such as the National Bioethics Advisory Commission19 and the
National Academies20 have called on Congress to address issues related to the human
subject protection through legislation.
Proposed Legislation. Several bills have been introduced on topics related
to the Common Rule. In the 109th Congress, Representative Pete Stark introduced
legislation on a topic related to the Common Rule: reporting of adverse events related
to drugs submitted for FDA approval or approved by FDA. The bill, H.R. 870 (the
PhRMA Act of 2005) would create criminal penalties, including fines and
imprisonment, for drug manufacturers’ executives who knowingly conceal reports
of serious adverse drug experience.
In the 108th Congress, Representative Diana DeGette introduced H.R.3594, the
Protection for Participants in Research Act of 2003. This bill would have extended the
scope of 45 CFR 46, including the terms of the Common Rule, to all public as well as
private research, and would have required the HHS Secretary to harmonize the Rule with
FDA’s regulations. In the 107th Congress, Senator Edward Kennedy introduced S. 3060,
the Research Revitalization Act of 2002, and Representative DeGette introduced H.R.
4697, the Human Research Subject Protections Act of 2002, which was similar to
H.R.3594 (108th Congress). S. 3060 would have created national standards for protecting
human subjects in research that would have been overseen by a new HHS office: the
National Office of Human Research Protections. The standards would have applied all
of 45 CFR 46 to all research conducted in the United States, funded by the United States
For additional information regarding clinical trials reporting and publication, see CRS
Report RL32832, Clinical Trials Reporting and Publication, by Erin D. Williams.
In 1995, President Clinton established the National Bioethics Advisory Commission
(NBAC) by Executive Order, to identify broad principles to govern the ethical conduct of
research, among other things. NBAC’s charter expired in 2001.
The National Academies is an organization comprising four non-profit institutions (the
National Research Council, the National Academy of Sciences, National Academy of
Engineering, and Institute of Medicine) that provide science, technology and health policy
advice under a congressional charter. See [http://www.nationalacademies.org], visited Apr.
government, or subject to United States regulatory review. In addition, the bill would
have required accreditation of IRBs, voluntary cooperative IRB review for multi-site
research, identification of countries with human subject protections that were
substantially equivalent to the United States for studies conducted overseas, and
disclosure of financial conflicts of interest by investigators and IRB members. Finally,
S. 3060 would have made enforcement action possible in district court against
investigators, sponsors, or the IRB for failure to comply with the regulations.
Report Contents. This report contains several sections, assembled to provide
a comprehensive overview of the Common Rule. The first section explores the
history of the Rule, focusing on issues and foreign and domestic policies that led to
its creation. The second section explores the current issues, studies and proposals
that have been made with respect to the Rule. Topics include the Rule’s scope, its
treatment of vulnerable populations, its governance of IRBs, its mechanisms for
addressing mistakes and misconduct, human subjects’ access to medical care, and
mechanisms for ongoing research on the Rule. Appendix A explores the interaction
of the Privacy Rule and FDA regulations with the Common Rule. Appendix B
contains a detailed history of the evolution of human subjects protections leading up
to the Common Rule.
History of the Common Rule
and Current Regulations
Research conducted on human beings is governed by a series of international
codes, national legislation, and agency regulations. The regulatory framework has
evolved over time, often shifting in the aftermath of tragedy. The following is a
timeline of seminal events that led to the creation of the Common Rule. A more
detailed historical overview is contained in Appendix B: History and
Requirements of the Common Rule.
Prior to 1940s:
! Physicians self-regulate their research using the Hippocratic Oath.
The Nuremberg Code is created by the international community after
the Holocaust, for the first time requiring individual research
subjects’ informed consent. The Code was not specifically adopted
into US law, but later became the basis of the Common Rule.
The United States’ National Institutes of Health (NIH) opens its
Clinical Center, and the DHEW Secretary issues Group
Consideration of Clinical Research Procedures Deviating from
Accepted Medical Practice or Involving Unusual Hazard, requiring
peer review of intramural human subjects research. Research funded
by NIH was not covered by this rule unless it was conducted there.
The Secretary of Defense, Charles Wilson, issued a Top Secret
memorandum establishing policy for research related to atomic,
biological, and chemical warfare. The policy incorporated the
principles of the Nuremberg Code and two additional protections —
a prohibition on research involving prisoners of war and a
requirement that the Secretary of the appropriate military service
approve research studies.
Thalidomide, a drug provided experimentally to pregnant women in
the United States, is linked to the birth defect phocomelia.21
Congress enacts the Drug Amendments of 1962 (P.L. 87-781),
requiring researchers to obtain subjects’ informed consent before
conducting research on them, and requiring Food and Drug
Administration (FDA) to review the safety and efficacy of new drugs
before they are sold in the United States.
A federally funded study of United States medical schools concludes
that internal institutional regulation of human subjects research is
The World Medical Association, an international group of
physicians, creates the Declaration of Helsinki, to help engender
public trust in biomedical research. The Declaration is a statement
of ethical principles to provide guidance to investigators and
participants in human subjects research.
NIH’s research resource division warns the Director of “possible
repercussions” due to the absence of an applicable code of conduct
for research, among other things.
Researcher Henry Beecher publishes 22 detailed cases of studies that
contained serious or potentially serious ethical violations, some
resulting in the preventable deaths of patients.
The United States Surgeon General publishes the policy Clinical
Investigations Using Human Subjects, requiring prior committee
review for all Public Health Service-funded human subjects
research, expanding the regulations to cover extramural research.
The responsibility for education and enforcement of the Surgeon
General’s policy falls to the Institutional Relations Branch of the
Division of Research Grants for the National Institutes of Health
Phocomelia Syndrome is a birth defect that may occur sporadically, or occasionally may
be inherited. In some cases it may be caused by exposure to toxins, such as certain drugs
(e.g., thalidomide) taken by a pregnant woman. It is characterized by missing or deformed
arms and/or legs. Other symptoms may include growth and mental deficiencies, and defects
in the eyes, ears, and nose. For further information, see [http://my.webmd.com/hw/health_
DHEW provides guidance about how to apply the Surgeon General’s
1966 policy, in Institutional Guide to DHEW Policy on Protection
of Human Subjects, listing the elements of informed consent, and
requiring continual review of ongoing research projects.
The public learns about the United States Public Health Servicefunded Tuskeegee syphilis study, in which researchers withheld
treatment from affected African-American men for 40 years, 19
years past the discovery of penicillin, which can cure the disease.
A DHEW ad-hoc advisory panel to review Tuskeegee finds that the
study was ethically unjustified, and recommends that Congress
create a permanent body with authority to regulate all federally
supported and conducted human subjects research.
The NIH Director creates the Office for Protection from Research
Risks (OPRR) from the IRB/DRG/NIH and locates it in his office.
DHEW replaces its 1966 policy and 1971 guidance with
comprehensive regulations governing the protection of human
subjects, forming Subpart A of 45 CFR 46.
Congress passes the National Research Act (P.L. 93-348), which
creates the National Commission for the Protection of Human
Subjects of Biomedical and Behavioral Research (the National
Commission) and directs it to make recommendations to the DHEW
Secretary about the ethical principles that should underlie human
subjects research. The act also requires grantees and contractees
under the Public Health Service Act to establish IRBs to review
research involving human subjects.
The DHEW Secretary publishes regulations with additional
protections for research involving fetuses, pregnant women, and
human in vitro fertilization (40 Federal Register 33526), forming the
initial version of Subpart B of 45 CFR 46.22
The DHEW Secretary publishes regulations with additional
protections for prisoners who are subjects in to biomedical and
behavioral research (45 Federal Register 53655), forming the initial
and current version of Subpart C of 45 CFR 46.
The DHEW Secretary publishes proposed regulations for research
involving those who are institutionalized as mentally disabled. (43
Subsequent changes were incorporated January 11, 1978 (43 FR 1758), November 3, 1978
(43 FR 51559), June 1, 1994 (59 FR 28276), and November 13, 2001 (66FR 56775). Only
the most recent 2001 revision is listed in the timeline above.
Federal Register 53950) These proposed regulations were not
The National Commission publishes the Belmont Report,
articulating three ethical principles of biomedical research: (1)
respect for persons, (2) beneficence, and (3) justice.
FDA publishes regulations that govern the protection of human
subjects in trials conducted to support an application to market a
product (45 Federal Register 36390). The regulations form 21 CFR
DHEW officially becomes HHS.
In response to the Belmont Report, HHS revises its human subjects
regulations (45 CFR 46, Subpart A).
FDA published regulations that govern the operations and functions
of IRBs in reviewing trials conducted to support an application to
market a product. (46 Federal Register 8975) The regulations form
21 CFR 56.
The President’s Commission for the Study of Ethical Problems in
Medicine and Biomedical and Behavioral Research issues
Implementing Human Research Regulations: The Adequacy and
Uniformity of Federal Rules and of Their Implementation (the
Commission Report), analyzing the rules and procedures of the
Federal entities conducting or supporting human subjects research.
It concludes that 45 CFR 46 (Subpart A) is the benchmark policy for
The HHS Secretary publishes regulations with additional protections
for children involved as research subjects (48 Federal Register
9818), forming the initial version of Subpart D of 45 CFR 46.
In response to the Commission Report, Subpart A of 45 CFR 46
(basic HHS Policy for Protection of Human Research Subjects) is
adopted by 16 federal agencies, and at that point becomes known as
the Common Rule.
The HHS Secretary updates protections for children involved as
research subjects (56 Federal Register 28032), forming the current
version of Subpart D of 45 CFR 46.
President Clinton issues a memorandum on February 17
(Memorandum for the Vice President, the Heads of Departments of
Executive Agencies, Subject: Review of Federal Policy for the
Protection of Human Subjects), directing each department and
agency of Government to review present practices to assure
compliance with the Federal Policy for the Protection of Human
Subjects and to cease immediately sponsoring or conducting any
experiments involving humans that do not fully comply with the
Congress passes the Health Insurance Portability and Accountability
Act of 1996 (HIPAA) that includes a requirement that the HHS
Secretary establish rules to protect the privacy of consumers’ health
The HHS Secretary issues the Privacy Rule pursuant to HIPAA,
establishing a set of basic consumer protections for certain healthrelated entities’ uses and disclosures of consumers’ protected health
HHS replaces OPRR with the Office for Human Research
Protections (OHRP) and elevates the office from NIH to HHS.
The HHS Secretary updates Subpart B of 45 CFR 46 (66 Federal
Register 56775-56780) to the version currently in force, continuing
the special protections for pregnant women and human fetuses and
making limited changes in terminology referring to neonates,
clarifying provisions for paternal consent when research is
conducted involving fetuses, clarifying language that applies to
research on newborns of uncertain viability, and correcting technical
The HHS Secretary amends the Privacy Rule, adding the
requirement that health care providers make a good faith effort to
obtain a written acknowledgment of receipt of the provider’s privacy
notice from those whom they treat directly.
and Proposed Legislation
The conduct of research has been transformed by many factors since 45 CFR 46
was first adopted in 1974. Key changes include the growth in both federally and
industry-sponsored biomedical research, which has resulted in a much larger and
more complex enterprise. To address the issues raised by the shifting research
landscape, a number of key reports have been published. (See Table 1 for a list of
key reports). The reports have raised issues and made recommendations in a number
of areas. Broadly, the issue areas include the scope of the Common Rule, treatment
of vulnerable populations, IRB issues, preventing mistakes and misconduct,
addressing injuries and medical care, and handling the future of human subjects
protections. The sections that follow provide an overview of the dilemmas defined
and recommendations made in the key reports.
Table 1. Key Human Subjects Protection Reports, 1995-2004
— Advisory Committee on Human Radiation Experiments Report (Advisory Committee
on Human Radiation Experiments) at
— Scientific Research: Continued Vigilance Critical to Protecting Human Subjects
(General Accounting Office - GAO) at [http://www.gao.gov/archive/1996/he96102t.pdf]
— Institutional Review Boards: Their Role in Reviewing Approved Research (HHS
Office of the Inspector General - OIG) at [http://oig.hhs.gov/oei/reports/oei-01-9700190.pdf]
— Institutional Review Boards: Promising Approaches (OIG) at
— Institutional Review Boards: The Emergence of Independent Boards (OIG) at
— Institutional Review Boards: A Time for Reform (OIG) at
— Final Report on Low-Volume Institutional Review Boards (OIG) at
— Research Involving Persons with Mental Disorders That May Affect Decisionmaking
Capacity (National Bioethics Advisory Commission - NBAC) at
— Research Involving Human Biological Materials: Ethical Issues and Policy Guidance
(NBAC) at [http://www.bioethics.gov/reports/past_commissions/nbac_biological1.pdf]
— Protecting Human Research Subjects: Status of Recommendations (OIG) at
— Recruiting Human Subjects: Pressures in Industry-Sponsored Clinical Research (OIG)
— Recruiting Human Subjects: Sample Guidelines for Practice (OIG) at
— Ethical and Policy Issues in International Research: Clinical Trials in Developing
Countries (NBAC) at
— Ethical and Policy Issues in Research Involving Human Participants (Aug. 2001;
NBAC), at [http://www.bioethics.gov/reports/past_commissions/nbac_human_part.pdf]
— Preserving Public Trust: Accreditation and Human Research Participant Protection
Programs (Institute of Medicine - IOM - Committee) at
— Clinical Trial Websites: A Promising Tool to Foster Informed Consent (OIG) at
— Responsible Research: A Systems Approach to Protecting Participants (IOM
Committee) at [http://www.iom.edu/report.asp?id=4459]
— Transcripts on research ethics (President’s Council on Bioethics - PCBE) at
— Protecting Participants and Facilitating Social and Behavioral Sciences Research
(National Research Council - NRC Panel) at [http://www.nap.edu/catalog/10638.html]
— The Ethical Conduct of Clinical Research Involving Children (IOM Committee) at
— Intentional Human Dosing Studies for EPA Regulatory Purpose (NRC, National
Academy of Sciences - NAS) at [http://books.nap.edu/catalog/10927.html]
— The Ethical Conduct of Clinical Research Involving Children (IOM Committee) at
Scope of the Common Rule
The protections and restrictions afforded by the Common Rule do not apply to
all research. Questions have been raised regarding which research should be
governed by the Common Rule, and the effect that the rule has on some specific
types of research.
Non-Federally Funded Research and Federally Funded Research
Outside the Scope of the Common Rule. The Common Rule governs only
research funded by agencies that have adopted 45 CFR 46, Subpart A. This
limitation may be important, as it has been reported that industry, rather than the
federal government, provides an estimated seventy percent of the funding for clinical
drug trials conducted in the United States.23 Other federal regulations that may apply
to human subjects research are also limited in their application. FDA requirements
only extend protections to clinical trials that support applications to market a medical
product, or other areas over which FDA has jurisdiction, regardless of funding
source. The HIPPA Privacy Rule’s protections only regulate the flow of personally
identifiable information, and extend only to non-background research conducted by
covered entities, such as hospitals or medical clearing houses. Because of these
limitations, some clinical research (for example, a doctor’s non-federally funded
study to compare methods of plastic surgery)24 falls outside the scope of HHS, FDA,
and HIPAA regulations, and therefore is not subject to federal informed consent and
IRB review requirements.25 Information is not generally collected about human
subjects studies that fall outside the scope of federal regulations, so the precise
number of these studies is not known; however, a few sensational cases have been
reported in the media.26
Companies and other organizations may voluntarily choose to apply the
Common Rule and/or 45 CFR 46 to their research projects. However research
projects in which compliance is voluntary are not subject to oversight or disciplinary
action by the HHS. In Responsible Research: A Systems Approach (Responsible
Research),27 the IOM recommended that federal protections such as requirements for
IRB approval and informed consent extend to every research project that involves
human participants, regardless of funding source or research setting. NBAC also
addressed this issue in Ethical and Policy Issues in Research Involving Human
Participants28 (Human Participants). In 2001, NBAC recommended a unified,
comprehensive federal policy embodied in a single set of regulations and guidance
that would apply to all types of research involving human participants (which would
unify the requirements of Common Rule, FDA regulations and HIPAA) and
legislation to create a single independent federal office to lead and coordinate the
See, e.g., Michelle Mello, et al., “Academic Medical Centers’ Standards for Clinical-Trial
Agreements with Industry,” The New England Journal of Medicine, vol. 351, no. 21, p. 2202
(May 26, 2005).
P.J. Hilts, “Study or Human Experimentation? Face-Lift Project Stirs Ethical Concerns.”
New York Times, June 21, 1998, p. A-25.
Health care institutions and universities generally have their own IRBs and requirements
for IRB review of research, which may exceed federal requirements. However, an infraction
of institutional policies does not itself constitute a breach of federal policy, and federal
agencies would not have the jurisdiction to enforce compliance with the institutional policy.
Also of note, a doctor’s failure to obtain informed consent prior to performing a medical
procedure — whether experimental or not — may give rise to one or more causes of action
under state law, enabling the patient to sue for battery and/or malpractice.
See, e.g.. cases listed by National Bioethics Advisory Commission, Ethical and Policy
Issues in Research Involving Human Participants, Aug. 2001, pp. 3-4.
Committee on Assessing the System for Protecting Human Research Participants, Institute
of Medicine, Responsible Research: A Systems Approach, (Washington: National
Academies Press, 2002).
NBAC, Ethical and Policy Issues in Research Involving Human Participants, Aug. 2001.
Clinical Trials in Developing Nations. As the pace and scope of
international collaborative biomedical research have increased, longstanding
questions about the ethics of designing, conducting, and following-up on
international clinical trials have reemerged. Some of these issues have taken center
stage because of the concern that research conducted by investigators and sponsors
from more prosperous nations in poor nations that are heavily burdened by disease
may, at times, be seen as imposing ethically inappropriate burdens on the host
country and on those who participate in the research trials.29 In its April 2001 report,
Ethical and Policy Issues in International Research: Clinical Trials in Developing
Countries,30 NBAC referred to these poor nations in which research is increasingly
being conducted as developing countries, where local technical skills and other key
resources are in relatively scarce supply. The following factors are among those that
NBAC cited as often leading to bioethical dilemmas posed by research conducted in
Special challenges arise from the combined effects of different
countries’ distinctive histories, cultures, politics, judicial systems,
and economic situations.
In countries in which extreme poverty afflicts so many, primary
health care services generally are inadequate, and a majority of the
population is unable to gain access to the most basic and essential
health products and services, so the people in these countries are
often more vulnerable in situations (such as clinical trials) in which
the promise of better health seems to be within reach.
Making a determination about the appropriate design for a clinical
trial depends on various contextual considerations, so that what
might be an ethically acceptable design in one situation could be
problematic in another. For example, it might be unethical to
conduct a clinical trial for a health condition in a country in which
that condition is unlikely to be found. In comparison, the same trial
might be quite appropriately conducted where the trial results could
be important to the local population.
In some countries, the methods used in United States — based
studies for identifying appropriate groups for study, enrolling
individuals from those groups in a protocol, and obtaining informed
voluntary consent might not succeed because of different cultural or
social norms. Meeting the challenge of developing alternative
methodologies requires careful attention to the ethical issues
involved in recruiting research participants and obtaining their
consent, which is necessary in order to ensure justice in the conduct
of research and to avoid the risk of exploitation.
NBAC, Ethical and Policy Issues in International Research: Clinical Trials in Developing
Countries, Apr. 2001, letter of transmittal to the President.
NBAC, Ethical and Policy Issues in International Research: Clinical Trials in Developing
Countries, Apr. 2002.
Discussions among those in the bioethics community have focused on the
question of whether the existing rules and regulations that normally govern the
conduct of United States investigators or others subject to United States regulations
remain appropriate in the context of international research, or whether they
unnecessarily complicate or frustrate otherwise worthy and ethically sound research
projects. Presently, regardless of where human subjects research is conducted
(domestically, in a foreign country, or in a developing nation), the Common Rule’s
requirements apply if it is funded by a United States agency that has adopted the
Rule. In such cases, a department or agency head may approve the substitution of
comparable foreign procedures in lieu of those required by the Common Rule. (45
CFR 46.101(h)) Since 1991, no such substitution appears to have been made.31 The
questions raised by NBAC and others are, what standards should such a Department
or Agency head use to determine whether foreign procedures are comparable — and
is the comparability of standards always necessary?
Fewer questions have been raised regarding the application of FDA’s and the
Privacy Rule’s regulations to research in developing nations. Whether clinical trials
are carried out within the United States or abroad, FDA only regulates those that are
conducted under an investigational new drug application (IND), which is FDA’s
approval for a sponsor to conduct a clinical trial. However, by contrast to the
Common Rule’s requirements, even if a foreign trial were not conducted under an
IND, FDA regulations would allow it to be used to support an FDA new drug
application (NDA — which is required to market a drug in the United States), if it
was conducted in accordance with the principles articulated in the Helsinki
Declaration, or the laws and regulations of the country in which the research was
conducted, whichever represents the greater protection of the individual.32 (21 CFR
312.120) The HIPAA Privacy Rule would not likely apply to a study conducted in
a developing nation (unless it involved a domestic covered entity handling personally
identifiable health information), and has no special provisions relating such research.
Center Watch, a clinical trials listing service, has reportedly found that
20%-30% of clinical trials are being conducted in developing nations.33 Between
1995 and 1999, the percentage of NDA submissions to FDA using foreign data rose
from 9% to 27%, and the number of foreign persons participating in NDA clinical
In March 2005, OHRP posted for public comment a framework for comparing oversight
of research involving human subjects in foreign institutions with United States protections.
(70 Federal Register 15322 [Mar. 25, 2005])
The Declaration of Helsinki is available online at [http://www.wma.net/e/policy/b3.htm],
visited Apr. 11, 2005. In June 2004, FDA issued a new proposed rule, which, if adopted,
would replace the requirement that foreign studies be conducted in accordance with ethical
principles stated in the Declaration of Helsinki with a requirement that the studies be
conducted in accordance with good clinical practice, including review and approval by an
independent ethics committee. (FDA Proposed Rule: “Human Subject Protection; Foreign
Clinical Studies Not Conducted Under an Investigational New Drug Application,” 69
Federal Register 32467 (June 10, 2004).
Information about CenterWatch is available from [http://www.centerwatch.org/
aboutcw.html], visited Apr. 11, 2005.
trials rose from 4,000 to 400,000, by one estimate.34 A variety of articles have
explored issues and efforts involved with these trials.35 Companies reportedly favor
clinical trials in developing nations, because it is easier to find patients and
physicians who are eager to participate, and less expensive because there are fewer
regulatory demands. Some foreign patients may see clinical trials as their best
chance for medications. Foreign doctors may find participation appealing because
of money they can get as clinical investigators and free medical equipment supplied
by drug companies.
Ethical issues involved in international clinical trials can be complicated by the
intersection of different social and cultural norms, clinical practices, applicable rules,
and regulatory bodies.36 Commentators have noted the importance of addressing
these differences equitably, particularly when a proposed clinical trial is to be
conducted in a developing nation where less robust subject protections may be in
The NBAC addressed the topic of clinical trials conducted in developing
nations, focusing on whether and how it would be ethical to apply the requirements
of the Common Rule made recommendations for the following five areas:38
The ethical conduct of clinical trials (e.g., review by an ethics committee,
individual informed consent, and adequate care for injuries).
The selection of research design and the relevance of routine care (e.g.,
providing care comparable to that in the United States rather than the host
The fair and respectful treatment of participants (e.g., mechanisms such as
consultation with community representatives to inform researchers about
cultures and customs of the population from which research participants will be
recruited; and culturally appropriate ways to disclose information.)
Melody Lin, Deputy Director of OHRP, Director of OIA, “Future Directions for Human
Subject Protections in International Research,” Presented in Sofia, Bulgaria, June 3-6, 2003,
visited Apr. 11, 2005.
For further descriptions of clinical trials in developing nations, see Gina Kolata,
“Companies Facing Ethical Issue as Drugs are Tested Overseas,” New York Times, Mar. 5,
2004, p. A1; Mary Jo Lamberti, “Going Global,” Applied Clinical Trials, June 1, 2004;
Xavier Bosch, “Clinical Trials Partnership Seeks to Boost Research in Developing
Countries,” Journal of the American Medical Association, vol. 292, no. 11 (Sept. 15, 2004),
See, e.g., Marilyn Chase, “Key AIDS Study In Cambodia Now in Jeopardy,” Wall Street
Journal, Aug. 12, 2004, p. B1.
See, e.g., The Participants in the 2001 Conference on Ethical Aspects of Research in
Developing Countries, “Moral Standards for Research in Developing Countries: From
‘Reasonable Availability’ to ‘Fair Benefits’,” Hastings Center Report ,vol. 43, no. 3 (2004);
Lamberti, “Going Global,” Applied Clinical Trials, Jun. 1, 2004.
NBAC, Ethical and Policy Issues in International Research: Clinical Trials in Developing
Countries, Apr. 2001.
Access to post-trial benefits (e.g., new interventions proven to be effective from
the research should be made available to some or all of the host country
population beyond the research participants themselves); and
The protection of research participant in international clinical trials (e.g.,
evaluation by HHS’s Office for Human Research Protections (OHRP) and host
In 2004, the HHS Secretary’s Advisory Committee on Human Research
Protections (SACHRP) tasked a subcommittee with investigating issues involved in
international research. The subcommittee has yet to issue recommendations.
Human Biological Materials. The Common Rule does not apply to research
involving human biological materials39 (unless the research also involves the humans
themselves), so this research may be conducted with federal funding and without
donor informed consent, IRB review of research protocols, or institutional assurances
of compliance. Like the Common Rule, FDA’s regulations governing the conduct
of clinical trials would also not apply to research conducted on biological materials.
By contrast, the HIPAA Privacy Rule may apply to some of studies on human
biological materials. It would require the informed consent of sample donors if the
biological materials were deemed to be personally identifiable health information,
and if the research involved handling of that information by a covered entity.
As NBAC noted in Research Involving Human Biological Materials: Ethical
Issues and Policy Guidance40 (Human Biological Materials) biomedical researchers
often use human biological materials, such as cells collected in research projects,
biopsy specimens obtained for diagnostic purposes, and organs and tissues removed
during surgery, in order to facilitate their studies. The use of these materials in
biomedical research can raise questions similar to those involved in human subjects
research, centering upon issues of privacy and informed consent. Privacy can
become an issue when the biological materials are identified or coded,41 because
information derived from experimentation on the samples could potentially be linked
back to its donor. Informed consent becomes difficult to obtain when the future
use(s) of the biological materials is not known at the time of their collection, because
researchers cannot provide donors with complete information regarding the
undetermined future use(s).
NBAC included an exploration of issues of privacy and informed consent in
Human Biological Materials. Among NBAC’s recommendations was one that
HHS’ Office for Human Research Protections (OHRP) affirmed that biological specimens
are not human subjects in 2004: “Guidance on Research Involving Coded Private
Information or Biological Specimens,” OHRP HHS (Aug. 10, 2004), at
[http://www.hhs.gov/ohrp/humansubjects/guidance/cdebiol.pdf], visited Apr. 11, 2005.
National Bioethics Advisory Commission, Research Involving Human Biological
Materials: Ethical Issues and Policy Guidance, Aug. 1999.
Identified samples are “linked to personal information in such a way that the person from
whom the material was obtained could be identified.” Coded samples are “supplied by
repositories to investigators from identified specimens with a code rather than with
personally identifying information.” (Source: Human Biological Materials).
NIH’s Office for Protection from Research Risks (OPRR), the precursor to HHS’s
OHRP, should consider research conducted with coded or identified samples to be
research on human subjects and regulated by the Common Rule. NBAC also
recommended that OPRR consider research conducted with unlinked samples to be
regulated by the Common Rule, but eligible for exemption from review, and research
conducted with unidentified samples not to be regulated by the Common Rule.42 If
NBAC’s proposal were adopted, federally funded research with identifiable samples
would require informed consent (including the disclosure of mechanisms to protect
records’ confidentiality), IRB approval, and institutional assurances of compliance.
Social and Behavioral Research. The Common Rule’s requirements,
including IRB review and the documentation of informed consent, apply not only to
biomedical research, but also to social and behavioral research (SBR). The HIPAA
Privacy Rule and FDA’s regulations could conceivably also apply to some SBR (if
the research were conducted by a covered entity or if it were used to support an FDA
application, respectively), however regulatory concerns voiced by those in the SBR
community have focused primarily on the impact of the Common Rule.
Regarding the Common Rule, which was designed with a focus on biomedical
research, some SBR researchers have questioned whether it should apply to SBR, and
have expressed a desire to have regulations regarding their research carved out from
the Common Rule.43 This is primarily due to concerns that IRBs are assembled with
biomedical expertise, and a review process focused on that research may not be well
suited to review social and behavioral research. SBR researchers claim that
unnecessary delays often result because their protocols are not accepted for expedited
review, despite their assertion that expedited review would be commensurate with
the protocols’ level and type of risk (risk may be physical in biomedical research but
is usually limited to the areas of confidentiality and privacy for SBR). Those
involved with SBR have also stated that the mechanisms IRBs approve for obtaining
informed consent in SBR are both overly cumbersome and ineffective in their
research, because, they say, the consent process mandated by the Common Rule
focuses on documenting consent instead of ensuring informed, voluntary decisionmaking.
In 2003, a National Academies’ National Research Council Panel on
Institutional Review Boards, Surveys, and Social Science Research (IRBSSR)44
recommended that OHRP issue guidance for IRBs about what informed consent
requirements are appropriate for various forms of SBR, and about when SBR should
Unlinked samples “lack identifiers or codes that can link a particular sample to an
identified specimen or a particular human being.” Unidentified samples “are supplied by
repositories to investigators from a collection of unidentified human biological specimens.”
(Source: Human Biological Materials).
See, e.g., Joan S. Sieber, “Social and Behavioral Research with Human Subjects: Key
Issues for SACHRP and OHRP to Consider,” Presentation to the Secretary’s Advisory
Committee on Human Research Protections, Washington, D.C., Aug. 8, 2004.
Panel on Institutional Review Boards, Surveys, and Social Science Research, National
Research Council of National Academies, Protecting Participants and Facilitating Social
and Behavioral Sciences Research (Washington: National Academies Press, 2003).
be classified as minimal-risk research and eligible for expedited review. The
IRBSSR also recommended, among other things, funding research on enhancing
privacy protections.45 On a related topic, in 1999, the American Association for the
Advancement of Science convened a workshop and issued a report containing
recommendations regarding social and behavioral research conducted using the
Proposed Legislation affecting the Scope of the Common Rule.
H.R. 3594 (108th Congress) would have expanded the scope of the Common Rule
(which currently only regulates research funded by a federal agency that has adopted
the Rule), to all research that is in or that affects interstate commerce. In addition,
public entities and private academic institutions would not have been eligible for
federal funding unless they maintained or contracted for a comprehensive and
ongoing program to educate investigators and Board members on the protection of
human subjects in research. The bill would have also required written attestation that
the principal investigator was familiar and agreed to comply with the requirements
for protecting human subjects, including informed consent. In addition, the bill
would have required that information be provided to the subject on how to contact
OHRP to submit questions about the rights of subjects or to report concerns
regarding the research.
H.R. 3594 (108th Congress) would have required the HHS Secretary publish a
determination in the Federal Register, not later than 18 months after the enactment
of the act, specifying whether there were circumstances in which research that studied
human tissue or other types of clinical specimens, or that did not involve any
interaction with a living human should have been considered human subject research.
For SBR, the bill would have required each institution with an IRB to report annually
to the HHS Secretary the number of behavioral or social sciences research proposals
reviewed, and would have required the Director of OHRP to consult with experts in
biomedical, behavioral, and social sciences research in carrying out his or her duties.
In addition, the HHS Secretary would have been required to establish expanded
informed consent criteria that provided for the provision of full and complete
information relevant to the research to a prospective human subject (possibly to allow
informed consent to be modified for SBR).
S. 3060 (107th Congress) would have expanded the definition of covered
research(which would have triggered the application of all Subparts of 45 CFR 46)
to that conducted on human subjects conducted in the United States, funded by the
United States government or subject to federal regulatory review. The bill would
have established within HHS a National Office of Human Research Protections,
headed by a Director to be appointed by the Secretary of HHS. The Director would
In July 2004, SACHRP heard a series of presentations on protecting human subjects in
SBR. Presenters raised issues and made recommendations similar to those of the IRBSSR.
These are available online at [http://www.hhs.gov/ohrp/sachrp/mtgings/mtg07-04/
present.htm], visited Apr. 11, 2005.
Mark S. Frankel, Ph.D. and Sanyin Siang, “Ethical and Legal Aspects of Human Subjects
Research on the Internet,” (Nov. 1999), at
[http://www.aaas.org/spp/sfrl/projects/intres/report.pdf], visited July 11, 2005.
have been able to promulgate regulations to determine whether various types of
research were covered by 45 CFR 46, and whether the research involved greater than
With regard to research conducted overseas, S. 3060 (107th Congress) would
have required that the Director publish a list of countries with human research subject
protections comparable to those in the United States. Studies conducted in those
countries would have been reviewed by an ethics board for compliance. For
countries not on the list, the bill would have required review by both an ethics board
and an IRB for studies that posed greater than minimal risk to the participants.
Inclusion and Protection of Vulnerable Populations
Participation of vulnerable populations in research raise two types of concerns.
First, concerns of inclusion, which focus on the importance of integrating all
populations in research on drugs that may be prescribed to them. Second, concerns
of protection, which focus on the need to help ensure that vulnerable populations are
not coerced into participating in research, or mistreated during their involvement.
The Common Rule provides that IRBs should ensure that the selection of
subjects is equitable. In making this assessment the IRB should take into account the
purposes of the research and the setting in which the research will be conducted and
should be particularly cognizant of the special problems of research involving
vulnerable populations, such as children, prisoners, pregnant women, mentally
disabled persons, or economically or educationally disadvantaged persons (45 CFR
46.111(a)(3)). In its review of research involving these vulnerable populations, the
IRBs must give consideration to the inclusion of one or more individuals who are
knowledgeable about and experienced in working with these subjects (45 CFR
46.107(a)). When some or all of the subjects are likely to be vulnerable to coercion
or undue influence, additional safeguards must be included in the study to protect the
rights and welfare of these subjects (45 CFR 46.111(b)). For example, a prisoner
may feel incapable of refusing a request made by a guard or warden to sign an
informed consent document, or a child may be persuaded to do so without truly
understanding the meaning of participation in the study. In each of those cases, the
subjects may have signed documents, but could not have truly given informed
consent. In addition, Subparts B, C, and D of 45 CFR 46 contain specific regulations
governing research on pregnant women, prisoners, and children, respectively. FDA
regulations contain provisions regulating research on children (21 CFR 50.54,55),
and for the conduct of research in emergency situations (21 CFR 50.24). The HIPAA
Privacy Rule contains no special provisions with regard to vulnerable populations.
Exclusion of some populations from research has in the past stemmed from the
reluctance of both researchers and potential subjects. Researchers have been
disinclined to conduct research on diverse populations because they want to reduce
as many variables as possible (for example, accepting only subjects with the same
race, gender, and age) to streamline their trials. Potential subjects have been afraid
to participate in trials because they do not trust investigators, having heard about
abuses like those in the Tuskeegee syphilis study. In order to facilitate the informed
inclusion of vulnerable populations and others in research, in June 2005, OHRP
announced the launch of a new public education campaign, Taking Part in Research:
It’s Your Decision, to provide information about issues to consider when thinking
about participating in clinical trials and other research studies.47
The NBAC focused some attention on ensuring that all segments of society can
participate in research in Human Participants, calling for additional appropriate
protections for those who may be more susceptible to coercion or exploitation. In
order to protect these populations, NBAC recommended that federal policy promote
the inclusion of all segments of society in research, that guidance be developed on
avoiding harmful or coercive situations, and that sponsors and investigators design
research that incorporates appropriate safeguards to protect all prospective
Minorities. None of the federal regulations for the protection of human
research subjects (the Common Rule, 45 CFR 46, the Privacy Rule, and FDA
regulations) address issues of race. The Common Rule’s provision that calls for
equity in research subject selection lists prisoners, pregnant women, mentally
disabled persons, and economically or educationally disadvantaged persons — but
makes no reference to race (45 CFR 46.111(a)(3)). Barriers to the recruitment of
African Americans and other minority populations have been noted by a number of
researchers, and are reportedly economic, cultural, and trust-based.48 Such barriers
may lead to disparities in health outcomes. For example, African Americans are at
a higher risk for stroke, and yet treatment recommendations are based largely on
studies involving few African Americans.49
To address disparities in minority participation in research as well as a range of
other health issues, Congress passed the Minority Health and Health Disparities
Research and Education Act of 2000 (P.L. 106-525), elevating the Office of Minority
Health Research (created by the NIH Director in 1990) to the level of center, and
renaming it the National Center on Minority Health and Health Disparities. The
Center works to address and ease health disparities involving cancer, diabetes, infant
mortality, AIDS, cardiovascular illnesses, and many other diseases.50
Children. The Common Rule requires equity in research subject selection, but
also urges IRBs to be particularly cognizant of the special problems of research
involving children, among other groups (45 CFR 46.111(a)(3)). The Rule also
requires studies including children and other vulnerable populations to include
additional safeguards to protect the rights and welfare of these subjects (45 CFR
46.111(b)). A section of regulations that are not a part of the Common Rule,
OHRP, Public Outreach, website at [http://www.hhs.gov/ohrp/outreach/], visited July 12,
Mike Mitka, “Efforts Needed to Foster Participation of Blacks in Stroke Studies,” Journal
of the American Medical Association, vol. 291, no. 11 (Mar. 17, 2004), p. 1312.
DeJuran Richardson quoted in, Mike Mitka, “Efforts Needed to Foster Participation of
Blacks in Stroke Studies,” Journal of the American Medical Association, vol. 291, no. 11
(Mar. 17, 2004), p. 1311.
“What We Do,” National Center on Minority Health and Health Disparities, visited Mar.
1, 2005, at [http://ncmhd.nih.gov/about_ncmhd/what.asp], visited Apr. 11, 2005.
Subpart D of 45 CFR 46, generally specifies that research involving children must
involve the assent of the children and the permission of the parents, and contain some
added protections for the children.51 FDA and HHS regulations governing research
involving children are not identical, which has led to some problems, and to some
recommendations by the IOM and SACHRP.
HHS and FDA regulations. HHS regulations (45 CFR 46 Subpart D — not
a part of the Common Rule) and FDA regulations are parallel but not identical
regarding the protection of children in research. Both specify that research may be
conducted on children if they assent,52 their parents or guardians consent, and:
the research involves no more than minimal risk;
the potential direct benefit to the subjects outweighs the risk to
the research involves no more than slightly more than minimal
risk and is likely to yield generalizable knowledge about the
subject’s disorder or condition.53
These categories are relatively free from controversy, except that guidance has been
requested regarding what constitutes minor increase over minimal risk.54 However,
there is one other, more controversial category of allowable research on children:
research with a 407 determination, so named because of the section of HHS
regulations that govern it. This research:
is not eligible for conduct under any other provision (of HHS human
subjects protection regulations);
involves more than minimal risk to subjects;
does not present the prospect of direct benefit to the individual
is not likely to yield generalizable knowledge about the subjects’
disorder or condition; but
In 1997, the Department of Education (ED), which has a particular interest in research
involving children, adopted Subpart D — Additional Protections for Children Who Are
Subjects in Research. (35 CFR 97.401-409; adopted in 62 Federal Register 63221 (Nov. 26,
1997]) ED has also adopted the Common Rule (Subpart A), but has not adopted Subparts
B or C.
The term assent is used to describe a child’s agreement to participate in research. By
contrast, consent means not only agreement, but agreement that is based upon consideration
with a level of mental capacity and experience that the law generally does not presume a
person is capable of forming until reaching the age of majority. Therefore, the assent of
a child must be accompanied by the consent of a guardian.
45 CFR 46.404-406 (HHS) and 21 CFR 50.51-53 (FDA).
Secretary’s Advisory Committee on Human Research Protections, Alexandria, VA, Mar.
presents an opportunity to understand, prevent, or alleviate a serious
problem affecting the health or welfare of children.55
In addition to IRB approval, studies meeting the criteria for a 407 determination
must also gain approval from the HHS Secretary and/or FDA Commissioner,
depending on which regulations apply to the research. The approval process involves
consultation with a panel of experts in pertinent disciplines and an opportunity for
public review and comment. Like other studies involving children, the assent of the
subjects and consent of their parents is also required.
To help clarify the approval process in HHS, the HHS Secretary requested that
SACHRP recommend a procedure for conducting 407 reviews. In July 2004,
SACHRP sent a letter to the Secretary recommending that, following an IRB request
for 407 review, OHRP should screen the application to determine if a 407
designation is appropriate. If so, SACHRP asserted, OHRP should appoint a
non-FACA56 panel for the Secretary, consisting of experts in science, ethics,
pediatrics, and the disorder/condition under the study; and at least one public member
who can adequately represent and voice the interests of the subjects.57
To assist the FDA with the approval process and other matters, in August 2004,
the FDA announced establishment of the Pediatric Ethics Subcommittee. The
Subcommittee will address pediatric ethical issues, as well as IRB referrals to clinical
investigations involving children as subjects and IRB referrals that involve both FDA
regulated products and research involving children as subjects that is conducted or
supported by HHS.58
On May 26, 2005, OHRP issued guidance on the 407 review process.59 The
guidance focused on the following topics: (1) IRB findings necessary to submit a
protocol to OHRP for 407 consideration and/or review; (2) steps in the submission
process; (3) OHRP’s response to submissions; (4) the schedule and details for 407
panel review; and (5) potential outcomes of the 407 review process.
IOM Report. As requested in the Best Pharmaceuticals for Children Act of
2002 (P.L.107-109) the HHS Secretary contracted with IOM to generate a report
about clinical research involving children. The report, entitled Ethical Conduct of
45 CFR 46.407 (HHS) and 21 CFR 50.54 (FDA).
The Federal Advisory Committee Act (FACA) defines how federal advisory committees
operate. For further information, see CRS Report RL30260, Federal Advisory Committees:
A Primer, by Stephanie Smith.
Letter from Ernest D. Prentice to Secretary Thompson, July 8, 2004, at
[http://www.hhs.gov/ohrp/sachrp/pages3-7from08112004sec.pdf], visited July 11, 2005.
HHS, FDA, “Advisory Committee; Pediatric Advisory Committee; Formation of a
Pediatric Ethics Subcommittee,” 69 Federal Register 46153 (Aug. 2, 2004).
OHRP, “Children Involved as Subjects in Research: Guidance on the HHS 45 CFR 46.407
(“407”) Review Process,” (May 26, 2005), at
[http://www.hhs.gov/ohrp/children/guidance_407process.html], visited July 11, 2005.
Clinical Research Involving Children, was published in March 2004, and contained
the following recommendations:60
researchers and reviewers should evaluate research involving
minimal risk, minor increase over minimal risk, or specific health,
emotional or mental conditions in relation to every-day activities of
IRBs should ensure that there is an ongoing informed consent
process (accompanying the legally required informed consent
documentation) that meets the needs of multi-cultural or
multilingual families, those with severely injured children, and
research that qualifies for a waiver of parental permission;
IRBs should make sure that researchers implement a process for
requesting children’s assent and parental permission that are
developmentally appropriate to children and clarify parents’ roles in
IRBs, sponsors, and research institutions should adopt written
policies regarding payment for children’s participation in research,
specifying acceptable and unacceptable amounts and types of
HHS should develop and implement a plan for data collection and
regulatory refinement for research involving children;
organizations that accredit human research protection programs
should incorporate requirements specific to research on children;
Congress should enact a Federal law that governs all research
involving children; and
federal and state legislators should help support the development of
experts, materials, and resources about research in children.
Children who are Wards. In the spring of 2005, interest in research
involving children who are wards was generated by news reports that, in the 1980s,
NIH-funded studies tested antiretroviral AIDS therapies on HIV-positive foster
children. Concerns were raised that researchers had not provided the children with
the protections required for HHS-funded research or those that the research
institutions had promised to use, such as the appointment of advocates for the
children.61 Others stressed the positive points of the foster children’s inclusion —
that it ensured that they received some treatment for HIV (at a time when there was
no approved therapy) from world-class researchers at government expense, slowing
their rate of death and extending their lives.62 The controversy highlighted the
fundamental balance sought between wards’ and other vulnerable populations’
protection and inclusion in research: ensuring that those in vulnerable positions are
Committee on Clinical Research Involving Children, Board on Health Sciences Policy,
Institute of Medicine, The Ethical Conduct of Clinical Research Involving Children
(Washington: National Academies Press, 2004).
See, e.g., John Solomon, “Federal Researchers Tested AIDS Drugs on Foster Children
Without Basic Protection,” Chicago Sun-Times,May 5, 2005, at
[http://www.suntimes.com/output/health/cst-nws-aids05.html], visited May 31, 2005.
adequately shielded from coercion and abuse, with a process not so cumbersome that
it de facto excludes them from research. On May 18, 2005, the House Committee on
Ways and Means: Subcommittee on Human Resources held a hearing on Protections
for Foster Children Enrolled in Clinical Trials to investigate the issue.63
The Common Rule and the HIPAA Privacy Rule neither define nor use the
terms ward or guardian. While 45 CFR 46 also contains no definition of ward,
subpart D uses the term in the clause “children who are wards of the State or any
other agency, institution, or entity...” (45 CFR 46.409). Subpart D of 45 CFR 46
defines the term guardian as an individual who is authorized under applicable State
or local law to consent on behalf of a child to general medical care (46.402(e)).
(Subpart D, described in the preceding section on Children, provides additional
protections for children who are research subjects. Subpart D is not a part of the
Common Rule, but it has been adopted by the Department of Education, and FDA
has adopted parallel provisions in its own Subpart D.)
FDA defines the term ward as a child who is placed in the legal custody of the
State or other agency, institution, or entity, consistent with applicable Federal, State,
or local law (21 CFR 50.3(q)). FDA defines the term guardian as an individual who
is authorized under applicable State or local law to consent on behalf of a child to
general medical care when general medical care includes participation in research.
For purposes of Subpart D, FDA’s definition of guardian also includes individuals
authorized to consent on behalf of a children to participate in research (21 CFR
Wards who participate in research may have three layers of federal protection,
none of which would attach unless the research were federally funded or conducted
for FDA submission. First, both the Common Rule and FDA regulations contain
basic protections, noted in the Introduction to this report, that would apply to
research involving children who are wards, just as they apply to all covered human
subjects research. Second, the protections for children included in Subpart D would
lend additional protections to children who participate in covered research, including
Third, a provision in subpart D of both 45 CFR 46 and FDA regulations, which
provides special protections for wards (45 CFR 46.409; 21 CFR 50.56), may also
apply. The provision is triggered by the following two types of research conducted
on children who are wards: (1) that involving greater than minimal risk and no
prospect of direct benefit to individual subjects but likely to yield generalizable
knowledge about the subject’s disorder or condition (45 CFR 46.406; 21 CFR 50.53);
and (2) that not otherwise approvable which presents an opportunity to understand,
prevent, or alleviate a serious problem affecting the health or welfare of children (45
CFR 46.407; 21 CFR 50.54). If triggered, the wards provision has two requirements:
(1) that wards be included only if the research is related to their status as wards, or
is conducted in settings in which the majority of children involved as subjects are not
Hearing testimony is available online at
July 12, 1005.
wards; and (2) that the IRB require appointment of an advocate for each child who
is a ward, in addition to any other individual acting on behalf of the child as guardian
or in loco parentis. One individual may serve as advocate for more than one child.
The advocate is to be an individual who has the background and experience to act in,
and agrees to act in, the best interests of the child for the duration of the child’s
participation in the research and who is not associated in any way (except in the role
as advocate or member of the IRB) with the research, the investigator(s), or the
Prisoners. Those seeking to protect prisoners are wary of research on this
population because their lack of liberty and choice may interfere with their ability to
give meaningful consent. On the other hand, overly-stringent requirements can
prevent research that could be particularly effective for and/or in prison populations,
such as those related to transmission of the human immunodeficiency virus (HIV).
The Common Rule provides that when some or all of the subjects are prisoners
or members of other vulnerable populations, additional safeguards must be included
in the study to protect the rights and welfare of these subjects (45 CFR 46.111(b)).
Research involving prisoners that is funded by HHS is also governed by Subpart C
of 45 CFR 46 (not a part of the Common Rule): Additional Protections Pertaining
to Biomedical and Behavioral Research Involving Prisoners as Subjects.64 Subpart
C requires researchers working with prisoners to provide extra assurances that the
protocol is fair and that participation is not coerced through mechanisms such as
arbitrary intervention by prison authorities, or the offering of possible advantages of
such a magnitude that the prisoner’s ability to weigh the risks of the research against
the value of such advantages in the limited choice environment of the prison is
impaired (45 CFR 46.305(a)). The HHS Secretary must confirm that the purpose of
the study is generally focused on prisoners, prisons and/or incarceration. (45 CFR
46.306 (a)(2)). In addition, the IRB carrying out responsibilities under Subpart D
with respect to research involving prisoners is to have a majority of members with
no association with the prison(s) involved, and at least one member who is a prisoner
or a prisoner representative, except that where a particular research project is
reviewed by more than one IRB, only one Board need satisfy this requirement (45
CFR 46.304). Neither FDA regulations nor the HIPAA privacy rule have provisions
focused on research with prisoners.
A SACHRP subcommittee has reviewed Subpart C, and recommended that it
be totally revised to ensure that regulations do not obstruct ethically and scientifically
appropriate research involving prisoners for the benefit of prisoners and others.65
In 1994, the Department of Justice’s Bureau of Prisons, which has a special interest in
conducting research involving prisoners, adopted its own regulations regarding research
involving prisoners (Subpart B — Research), which are similar to, though more rigorous
than 45 CFR 46, Subpart C. (28 CFR 512.10-21; adopted at 59 FR 13860, Mar. 23, 1994,
as amended at 62FR 6661, Feb. 12, 1997) The Department of Justice (DOJ) has adopted the
Common Rule (Subpart A of 45 CFR 46). DOJ has not adopted 45 CFR 46’s Subparts B-D.
Ernest D. Prentice, “Update on HHS Advisory Committee on Human Research
protection,” presented at the Fourth National Medical Research Summit, Baltimore, MD,
However, having recognized that a total revision of Subpart C will take time, the
subcommittee recommended that, as an intermediate solution, the following portions
of the existing regulation be clarified:
the definition of prisoner — making it functional (so that it might
include, for example, persons in community corrections programs,
on probation, or on parole) rather than contingent on classifications
the applicability of Subpart C when incarceration occurs
the necessary qualifications of the prisoner representative on the
the scope of follow up care required after a study ends, when
incarceration ends or when it continues.66
Pregnant Women, Human Fetuses, and Neonates. The establishment
of appropriate rules to govern research on pregnant women, fetuses and neonates
involves balancing protections with requirements. Protections are necessary to
minimize the risk of harm, particularly given that neonates and fetuses are unable
make decisions about whether to participate in research. Requirements are necessary
to help ensure that treatments for women, fetuses and neonates are developed, and
that researchers do not avoid testing on these populations because of fear of harm to
the subjects and the potential for resulting litigation.
FDA regulations and the HIAA Privacy Rule have no special provisions
pertaining to research involving pregnant women, fetuses, or neonates. However, the
Common Rule provides that when some or all of the subjects are pregnant women
or other vulnerable populations, additional safeguards should be included in the study
to protect the rights and welfare of these subject (45 CFR 46.111(b)). In addition,
HHS regulations that are not a part of the Common Rule contain specific protections
for women, human fetuses, and neonates (45 CRF 46, Subpart B). Subpart B was
amended in 2001 to include additional protections for pregnant women, human
fetuses, and neonates.67 Subpart B now instructs IRBs to make determinations based
on a combination of factors, such as whether there is the potential for a direct benefit
to the woman, fetus, or neonate, whether there is more than a minimal level of risk,
and whether the neonate is viable (45 CFR 46.203-206). Neither the Common Rule,
Apr. 23, 2004.
Subpart C Subcommittee, “Issues Identified for Possible Short or Intermediate Term
Solutions,” presented to the Secretary’s Advisory Committee on Human Research
Protections meeting, Alexandria, VA, Mar. 2004; Subpart C Subcommittee, “DRAFT Subpart C,” presented to the Secretary’s Advisory Committee on Human Research
Protections meeting, Washington, DC, July 2004, at [http://www.hhs.gov/ohrp/sachrp/
mtgings/mtg07-04/present/subpartc_files/frame.htm], visited Apr. 11, 2005.
66 Federal Register 56776, Nov. 13, 2001.
nor Subpart B apply to embryonic research performed outside of the uterus, to in
In a continuing effort to strike the best regulatory balance, the HHS Secretary
has requested that SACHRP advise the HHS Secretary and OHRP on whether
Subpart B appropriately protects pregnant women, fetuses, and neonates in
consideration of the Belmont Principles of Beneficence, Justice, and Respect for
Persons.69 SACHRP’s work on the topic is ongoing.
Diminished Capacity. Diminished capacity for decision-making (a lessened
ability to make or express one’s autonomous choices) can be caused by permanent
conditions, such as dementia or retardation, as well as temporary situations, such as
accidents or emergencies that render victims unconscious for a time. Research on
populations with diminished capacity is complicated by the fact that potential
participants may not be capable of understanding and evaluating options, which are
necessary to be able to give informed consent. On one hand, some feel that
restrictions should be strong enough to protect members of the vulnerable
populations from abuse, which they may not be capable of avoiding or addressing
due to their diminished capacity. On the other hand, some note that if research on
these populations is restricted, treatments for emergency situations or for diseases
such as Alzheimer’s may never be pursued.
The HIPAA Privacy Rule contains an emergency use provision that allows for
disclosures to be made in some narrow circumstances without prior authorization if
authorization cannot practicably be provided because of the individual’s incapacity
or because of an emergency treatment circumstances (45 CFR 164.510(a)(3)) .70 The
Common Rule allows for consent to be given by a subject’s legally authorized
representative (LAR — persons empowered to give informed consent on behalf of
potential subjects with diminished capacity), and contains some exceptions to the
requirement that informed consent be documented (45 CFR 46.116 and 117(c)). In
addition, it allows an IRB to waive the requirement of an informed consent procedure
if it determines that (1) the research involves no more than minimal risk to the
subjects; (2) the waiver or alteration will not adversely affect the rights and welfare
of the subjects; (3) the research could not practicably be carried out without the
waiver or alteration; and (4) whenever appropriate, the subjects will be provided with
additional pertinent information after participation (45 CFR 46.116(c)) . By contrast
The Dickey Amendment (a rider that Congress has attached annually to the Labor, HHS,
and Education appropriations acts from FY1996 to the present) prohibits HHS from using
appropriated funds for the creation of human embryos for research purposes or for research
in which human embryos are destroyed. For further information about the Dickey
amendment and other restrictions related to embryo research, see CRS Report RL31015,
Stem Cell Research, by Judith A. Johnson and Erin D. Williams.
Ernest Prentice, “45 CFR 46 Subpart B Additional Protections for Pregnant Women,
Human Fetuses & Neonates Involved in Research,” Presentation to the Secretary’s Advisory
Committee on Human Research Protections, (July 27, 2004), Washington, DC.
In November 1978, DHEW (HHS’s predecessor) published Proposed Regulations on
Research Involving Those Institutionalized as Mentally Disabled, at 43 Federal Register
53,950 (Nov. 17, 1978). The proposed regulations were never adopted.
to the Common Rule,71 FDA regulations specifically allow for research to be
conducted without consent in emergency situations in which taking the time to obtain
the consent of either the subject or of his or her LAR would prove detrimental to the
subject (21 CFR 50.24).72 In June 2004, HHS published an advance notice of
proposed rulemaking on the topic: Additional Protections for Adults with Impaired
Decisionmaking Capacity. (69 Federal Register 37473 [June 28, 2004]).
In 1998, the NBAC investigated the topic of research on populations with
diminished capacity.73 Its report included extensive recommendations for the
selection of LARs, and the criteria the representatives should use to make surrogate
decisions. In addition, NBAC recommended the following for research involving
persons with diminished capacity:
it should only be performed if other populations (without diminished
capacity) could not be used;
protocols should include procedures designed to minimize risks to
an IRB may waive the informed consent requirement if a study
involves no more than minimal risk; and
researchers may conduct studies involving more than minimal risk
and no direct benefit to the subjects if they first obtain an evaluation
by a special panel convened by the HHS Secretary.
Proposed Legislation Affecting the Inclusion and Protection of
Vulnerable Populations in Research. H.R. 3594 (108th Congress) would have
required all research that was federally regulated and/or affected interstate commerce
to be conducted in accordance with 45 CFR 46 (including Subparts B-D which
provide special protections for certain vulnerable populations).74 In other words the
In 1997, President Clinton issued a memorandum to 19 Department and Agency heads
prohibiting the waiver of informed consent for classified research, among other things.
“Strengthened Protections for Human Subjects of Classified Research” Presidential
Memorandum (May 13, 1997), 10 U.S.C. § 1107, available at [http://www.eh.doe.gov/ohre/
On October 2, 1996 (61 Federal Register 51531), the Secretary, HHS, announced, under
Section 46.101(i), a waiver of the applicability of the 45 CFR Part 46 requirement for
obtaining and documenting informed consent for a strictly limited class of research,
involving research activities that may be carried out in human subjects who are in need of
emergency therapy and for whom, because of the subjects’ medical condition and the
unavailability of legally authorized representatives of the subjects, no legally effective
informed consent can be obtained. This provision applies only to HHS research and is not
a part of the Common Rule. See Gary B. Ellis and Melody Lin, “Subject: Informed Consent
Requirements in Emergency Research,” OPRR Reports, [no. 97-01], (Oct. 31, 1996), at
[http://www.hhs.gov/ohrp/humansubjects/guidance/hsdc97-01.htm], visited May 3, 2005.
NBAC, Research Involving Persons with Mental Disorders That May Affect
Decisionmaking Capacity, Dec. 1998, at [http://www.georgetown.edu/research/nrcbl/nbac/
capacity/Executive.htm], visited Apr. 11, 2005.
In cases in which both FDA and Common Rule regulations might apply, H.R. 3594 (108th
vulnerable populations protections contained in 45 CFR 46 would have been applied
to research conducted, funded or regulated by a federal agency — whether or not they
had previously adopted the Common Rule — and to those conducting research that
affects interstate commerce (meaning virtually all researchers in the United States).
This would have greatly expanded the reach of federal regulations governing research
with vulnerable populations.
On the topic of diminished capacity, not later than three years after the
enactment of the Act, the HHS Secretary would have been required to promulgate
regulations to enhance the protection of people with diminished decision making
capacity with respect to their participation as subjects in human subject research. In
addition, within 18 months of the enactment of the act, the Secretary would have
been required to complete a review of areas of difference between HHS and FDA
regulations on the topic of research relating to emergency interventions (which would
have often applied to persons with a diminished capacity for decision making),
among other things. Within that same time frame, the Secretary would have also
been required to publish a determination in the Federal Register regarding (i) whether
modified procedures should have applied to human subject research that posed
minimal risk to the subjects, including whether there were any types of such research
for which some aspect of the requirement of informed consent or documentation of
informed consent should have applied differently, and (ii) whether the list of
expedited procedures or the list of exemptions under the Common Rule should have
been modified or new categories of expedited procedures established. This may
have helped to create specific rules governing research on both persons with
diminished capacity and children.
Like H.R. 3594, S. 3060 (107th Congress) would have extended all of the
Subparts of 45 CFR 46 to all research conducted in the United States, funded by the
United States government or subject to United States regulatory review. For subjects
who underwent trauma and could not practically consent (one population with a
diminished capacity for decisionmaking), alternative means of obtaining consent
would have been sought as described in the FDA regulations, 21 CFR 50.24.
Institutional Review Boards (IRBs)
The Common Rule and FDA regulations charge IRBs with reviewing protocols
for human subjects research to ensure that the studies will be conducted with proper
protections for human subejcts. The HIPAA Privacy Rule relies either upon IRBs or
separate Privacy boards to carry out its function of protecting subjects’ health
Questions have been raised regarding IRBs’ membership,
responsibilities, and duties, and the extent of their registration with the federal
IRB Membership. IRB deliberations require expertise in both the scientific
underpinnings of proposed research and also in local customs and understandings
Congress) would have clarified that FDA’s definitions of vulnerable populations would
prevail. (H.R. 3594, proposed § 491A(b)(1)(C))
associated with being a research subject. Some have expressed concern regarding the
potential for bias in IRB deliberations when most members are affiliated with the
institution or company conducting research, and may have a vested interest in the
outcome.75 Finding the appropriate balance is important to ensure the scientific
validity of the study design while incorporating concerns of subjects.
The Common Rule (45 CFR 46.107) and FDA regulations (21 CFR 56.107) for
IRB membership are identical. The HIPAA Privacy Rule refers to IRBs and to the
Common Rule, but does not create new requirements for IRB membership. It does,
however, list the requirements of a privacy board’s membership — and many
institutions have their IRB serve as their privacy board. The HIPAA privacy board
membership requirements are a subset of the Common Rule’s requirements for IRB
membership (45 CFR 164.512(i)(1)(i)(B)).
In order to protect against the potential for pro-institution or pro-industry bias
in IRB deliberations, the IOM (in Responsible Research) and the NBAC (in Human
Participants) recommended that at least 25% of the IRB membership comprise
people unaffiliated with the institution, and at least 25% comprise non-scientists. If
adopted, these recommendations would increase the Common Rule’s current
requirement that an IRB have at least one member (of a minimum of five members)
from each of these categories. In addition, IOM and NBAC recommended that a new
requirement be added that at least 25% of an IRB’s members represent the local
community and/or the participant perspective. NBAC further recommended that
federal regulations specify standards that individuals must meet to be included on an
IRB Duties. According to the Common Rule and FDA regulations, an IRB is
tasked with the responsibility for protecting the rights and welfare of human subjects.
Increases in the scope of responsibility and number of protocols that IRBs review
have limited the depth with which some IRBs are able to consider human subjects
protocols. IRBs may find themselves tasked not only with protecting human
subjects, but also with other duties such as regulatory compliance, risk management,
conflict of interest reviews, and carrying out the functions of a HIPAA privacy
In Responsible Research, IOM noted that overloading IRBs, whose members are
generally not paid for their participation, “is a disservice to research participants.”
It recommended that the IRB focus its full committee deliberations and oversight
primarily on the ethical aspects of the protection of research subjects. Specifically,
it recommended that IRBs not be tasked with responsibilities that the Common Rule
does not require (e.g., managing institutional risk, ensuring institutional compliance
See, e.g., M. Cho and P. Billings, “Conflict of Interest and Institutional Review Boards,”
Journal of Investigative Medicine, vol. 45, no. 4 (1997), pp. 154-159; S. Peckman, “Local
Institutional Review Boards,” in NBAC Ethical and Policy Issues in Research Involving
Human Participants, vol. 2 (Bethesda, MD: NBAC, 2001).
A privacy board reviews a covered entity’s preparatory research that involves personal
health information to determine whether privacy protections are adequate (45 CFR
with all relevant research rules and regulations, and assessing potential conflicts of
interest with other units within the research program or organization), and that these
be assigned to other oversight bodies within an institution.
IRB Registration. By some estimates, there are at least five thousand IRBs
in the United States, but the exact figure is unknown because they are not all required
by the Common Rule,77 FDA regulations,78 or the HIPAA Privacy Rule79 to register
in a central location. In 1998, the HHS Office of the Inspector General (OIG) issued
several reports on IRBs, one of which contained the recommendation that IRBs
register with the Federal government.80
OHRP reviewed the OIG’s
recommendations, concluded that registration would be highly beneficial for
identifying, monitoring, and tracking IRBs for outreach activities, and began
registering IRBs in December 2000. OHRP required, among other things, a list of
IRB members, their representative capacities, and experience, and their employment
or other relationship(s) with the institution. OHRP currently posts all registered IRBs
on its website.81
On July 6, 2004, OHRP published a proposed rule in the Federal Register82 that
would create one IRB registration system for HHS (including both OHRP and FDA),
administered at a single website. The proposed new rule would require institutions
to provide additional information that OHRP currently requests but does not require.
This includes, for example, information regarding the accreditation status of the
institution or IRB organization, total numbers of active research protocols reviewed
by the IRB (including protocols supported by other Federal departments or agencies)
and the nature of those protocols, and IRB staffing.
OHRP gathers information about some IRBs under the terms of the Common Rule. If an
institution seeking federal funding opts to obtain a federal-wide assurance (which a funding
Federal Department or Agency must accept in lieu of the direct submission of an assurance),
the institution must provide information about its IRB (among other things) to OHRP. If the
institution does not seek a federal-wide assurance, it is required to submit such information
to the funding Department of Agency head rather than to OHRP (45 CFR 46.103(a); (b)(2)).
FDA could gather information about IRBs that review protocols for submission to FDA.
FDA requires IRBs to keep records and make them available for FDA inspection (21 CFR
The HIPAA Privacy Rule requires privacy boards and IRBs to keep records, but not to
register at a centralized location (45 CFR 164.512(i)(1)(i)(B)).
OIG, HHS, Institutional Review Boards: A Time for Reform, June 1998, at
[http://oig.hhs.gov/oei/reports/oei-01-97-00193.pdf], visited Apr. 11, 2005.
Office of Public Health and Science, HHS, Institutional Review Boards: Registration
Requirements, 69 Federal Register 40585 (July 6, 2004). The current OHRP IRB
registration form is available at [http://www.hhs.gov/ohrp/humansubjects/
assurance/regirb.htm], visited Apr. 11, 2005. Additional information about IRB registration
with OHRP is available at [http://www.hhs.gov/ohrp/assurances/], visited July 11, 2005.
Office of Public Health and Science, HHS, “Institutional Review Boards: Registration
Requirements,” 69 Federal Register 40585 (July 6, 2004).
Defining and Weighing Risks and Potential Benefits. Two of an IRB’s
primary responsibilities are to define and weigh a study’s risks and potential benefits.
The Common Rule and FDA regulations similar advice to IRBs on this topic. The
HIPAA Privacy Rule refers to the sections of the Common Rule that address risk,83
but does not raise new issues on the topic.
The Common Rule and FDA regulations both define minimal risk in the same
way. (45 CFR 46.102(i) (HHS); 21 CFR 50.3(f) (FDA)) However, the FDA
regulations and 45 CFR 46 Subpart D (which does not include the Common Rule)
use but do not define not define the term minor increase over minimal risk (45 CFR
46.406(a) (HHS); 21 CFR 50.53(a) (FDA)). In addition, both FDA regulations and
45 CFR 46 (including the Common Rule) leave the weighing of risks and potential
benefits in individual protocols up to local IRBs, enabling them to apply local
community standards. Thus, the IRB must discern what factors should be considered
in the risk/benefit equation.
One way potential benefits from research may be categorized is by their likely
recipients. A research study might have potential benefits for the research subjects,
for people in the same category as the research subjects, and/or for society in
general.84 Despite general ethical prohibitions against putting one group of people
at risk solely for the benefit of others, many observers have found that some small
amount of risk might be acceptable even if there is no predicted benefit to the
subjects. The National Research Council of the National Academies (NRC)
considered whether researchers could expose subjects to small amounts of pesticides
that are currently in use in order to establish their safety.85 Such a study would pose
some (minimal) risk to the subjects, but no potential benefit would flow to them or
to others in the same category. The only benefit would accrue to society. In this
case, the NRC found that health and environmental benefits to society could justify
“a somewhat higher risk level than that posed by studies for which there is no
identifiable risk or for which there is a reasonable certainty of no harm.” NRC
stressed that a risk of lasting harm is never justifiable.86
See, e.g., 45 CFR 164.512(i)(2)(iv)(a): “(A) An IRB must follow the requirements of the
Common Rule, including the normal review procedures. ...”
For example, a study with potential benefits for research subjects could be one conducted
on a child with leukemia designed to diminish the effects of his/her disease. A study with
potential benefits for individuals in the same category as research subjects could be an
observation of the disease process of leukemia in children. Such a study would not be
designed to benefit the children in the study, but rather to facilitate the future development
of treatments for other children with leukemia. A study with potential benefits for society
could be taking blood from children with leukemia in order to help develop a vaccine
unrelated to children or to leukemia. Such a study would not be designed to benefit the
children in the study or other children with leukemia, but rather society in general.
NRC, Intentional Human Dosing Studies for EPA Regulatory Purpose (Washington, DC:
The National Academies Press, 2004).
In a move that touched on the topic of weighing risks and potential benefits involved in
pesticide research, in Apr. 2005, the acting administrator of the Environmental Protection
Agency (EPA) cancelled a program (the Children’s Health Environmental Exposure
Others have voiced disagreement with NRC’s position, stating pesticide
experiments in human beings are “morally unconscionable and scientifically dubious
- they fail to meet fundamental standards of permissible research - as they offer no
potential therapeutic benefit to the subjects or society.”87 Opponents of pesticide
experimentation also claim that such experiments violate the Nuremberg Code and
all subsequent national and international codes of medical research ethics that were
adopted precisely to prevent potentially harmful experiments from ever again being
conducted on human beings.88
A parallel issue to whether studies with no therapeutic value and minimal risk
may be ethically conducted, is whether study participants can ethically be denied
known treatments and be placed on a placebo as a part of a control group in the
investigation of a new drug or treatment. While participation may benefit subjects
who receive the new drug, those in the placebo group may not benefit, and may
actually undergo some risk if denied a known treatment by their participation in the
study. According to ethicist Howard Brody, researchers may “deny part of the study
group a treatment known to be effective [as long as] subjects are not harmed in
seeking the goal of gaining new knowledge.”89 The NBAC drew a finer distinction
in Human Participants, stating that when placebos are used (and in all cases), IRBs
should limit the amount of social and physical risk that can be imposed, regardless
of the participants’ willingness to participate or the monetary (or other) enticement
being offered. Further, the possibility of some benefit from one element of a study
should not be used to justify otherwise unacceptable elements of research whose
potential benefits, if any, accrue solely to society at large.
Research Study) that was “designed to fill critical data gaps in the understanding of how
children may be exposed to pesticides (such as bug spray) and chemicals currently used in
households.” [http://www.epa.gov/cheers/], visited Apr. 13, 2005. The cancellation was
made following accusations that the study would have created unacceptable health risks to
children and disproportionate risks to low-income children among other things. See, e.g.,
[http://www.ibiblio.org/arc/programs/cheers.html], visited Apr. 13, 2005.
In the cancellation notice, the EPA Acting Administrator noted that many
misrepresentations about the study had been made, and added that EPA must conduct
quality, credible research in an atmosphere absent of gross misrepresentation and
On a related note, in Feb. 2005, the EPA published a proposed plan to establish a
comprehensive framework for making decisions about the extent to which it will consider
or rely on certain types of human subjects research, including that with pesticides. The plan
included a statement of EPA’s intention to pursue rulemaking, in which it may adopt all
subparts of 45 CFR 46 (70 FR 6661, Feb. 8, 2005). EPA adopted the Common Rule in
Testimony of Alliance for Human Research Protection President and Founder, Vera
Hassner Sharav, to the Committee on the Use of Third Party Toxicity Research with Human
Research Participants, Science, Technology, and Law Program, at NAS (Jan 8, 2003), at
[http://www.ahrp.org/testimonypresentations/EPApesticide.php], visited May 3, 2005.
Scott C. Jenkins, “Placebo Ethics Depend on Informed Consent, Scientific Value,
Michigan State’s Brody Asserts,” Washington Fax (Feb 23, 2004), p. 1.
Unlike the difficulty with estimating potential benefits, which rests in part on
the likely recipient, the difficulty with risk assessment lies in ensuring that the level
of risk triggers an appropriate level of review. Thorough review of protocols that
pose minimal risks to human participants may be conducted quickly, while those with
higher risk may require more scrutiny. As the number and variety of research
protocols involving human subjects has increased, some IRB members have called
for consistent, transparent guidance about oversight required for various categories
of human subjects research.
The NBAC addressed this issue in Human Participants, recommending that
Federal policy require an ethical review that is commensurate with the nature and
level of risk involved, and defining minimal risk as the probability and magnitude of
harms that are normally encountered in the daily lives of the general population. On
a related note, NBAC also recommended that each component of a study be
evaluated separately, and its risks should be both reasonable in themselves as well
as be justified by the potential benefits to society or the participants. Potential
benefits from one component of a study should not be used to justify risks posed by
a separate component of a study. This type of component analysis is not currently
required by or mentioned in the Common Rule, which directs IRBs to weigh the risks
and potential benefits of the entire study (See 45 CFR 46.111(a)(2)). In other words,
the Common Rule allows an IRB to justify an increased risk posed by one portion of
a research study, by a benefit gleaned from a separate portion of a research study, or
by the entire study.90
The IOM investigated the issue of levels of review in Responsible Research.
It recommended that the degree of scrutiny, the extent of continuing oversight, and
the safety monitoring procedures for research proposals should be calibrated to a
study’s degree of risk. Specifically, IOM recommended that OHRP coordinate the
development of guidance for risk stratification, and develop and disseminate best
practices in order to lessen the extreme variability in the approval decisions and
regulatory interpretations among IRBs.
IRB Shopping. A second potential issue concerns the local flexibility that the
Common Rule and FDA regulations (and the HIPAA Privacy Rule, by cross
reference to the Common Rule) give to IRBs in determining and weighing risks and
benefits. The Common Rule and FDA regulations require an institution, or when
appropriate an IRB, to prepare and maintain adequate documentation of IRB
activities (45 CFR 46.115 (HHS); 21 CFR 56.115 (FDA)), but contain no
requirement that a researcher, institution, or any other party inform an IRB if a study
was previously disapproved by another IRB. The local flexibility that individual
IRBs have may thus lead to “IRB shopping” — a situation in which sponsors and/or
A form of component analysis was recommended by the SACHRP Research Involving
Children Subcommittee (focused on research conducted under 45 CFR 46 Subpart D, which
is not a part of the Common Rule). The subcommittee suggested that each research
procedure in a treatment study be independently evaluated in terms of benefits and risks to
subjects. The recommendation generated a great deal of discussion and no consensus at the
April 2005 SACHRP meeting. [http://www.hhs.gov/ohrp/sachrp/], visited Apr. 20, 2005.
research investigators who are unhappy with one IRB’s reviews switch to another
without the new IRB being aware of the other’s prior involvement.
Concerns about IRB shopping are twofold. First, there is the concern that the
practice may deprive the new IRB of information that may be important for
protecting human subjects. Second, there is the worry the practice might enable
sponsors and clinical investigators to ignore rather than address the concerns raised
by an unfavorable IRB review decision.91 Some reports of IRB shopping were
included in the OIG’s 1998 report Institutional Review Boards: A Time for Reform
(Reform Report), which stressed that seeking a second IRB’s approval was
acceptable, but suggested that the second IRB should be informed about the actions
of the first.
In response to the OIG report, in 2002 FDA issued an advance notice of
proposed rulemaking (Institutional Review Boards: Requiring Sponsors and
Investigators to Inform IRBs of Any Prior IRB Reviews, 67 Federal Register 10115)
The proposed rule would require sponsors and investigators to inform IRBs about any
prior IRB review decisions. Among other things, the notice called for comments,
particularly on the question of how often IRB shopping actually occurs, and whether
the proposed rule would be beneficial.
FDA received a range of responses. Some, such as the Applied Research Ethics
National Association (ARENA), supported the requirements — stressing that FDA
should make it incumbent on sponsors (not IRBs) to provide the information.92
Others, such as the Biotechnology Industry Organization (BIO), wrote that because
no evidence suggests that IRB shopping is a common occurrence, a reporting
requirement would add an unnecessary administrative burden to IRBs.93 Still others,
such as the American Society of Gene Therapy (ASGT), suggested that, even if it is
established that IRB shopping occurs, it may occur for benign reasons.94 For
example, while it may be that sponsors seek IRBs with less expertise or rigor in
hopes that they will approve studies, the opposite may also be true — that IRBs
inexperienced in certain areas may choose to disapprove trials which they are
One additional group, the Association of American Medical Colleges (AAMC),
pointed out that medical schools and teaching hospitals are not able to conduct
research with human participants that has not been approved by their institutional
FDA, Institutional Review Boards: Requiring Sponsors and Investigators to Inform IRBs
of Any Prior IRB Reviews, Docket No. 01N-0322. (67 FR 10115, Mar. 6, 2002)
Letter from Daniel Nelson, President, ARENA President, et al., to FDA June 4, 2002, at
Apr. 11, 2005.
Letter from Michael Werner, Vice President, Bioethics, BIO, to FDA, Apr. 6, 2002, at
Apr. 11, 2005.
Letter from Malcolm Brenner, President of the ASGT, to FDA, May 24, 2002, at
onse.html], visited Apr. 11, 2005.
IRB — so there is no incentive to IRB shop.95 However, in multi-site trials (where
multiple IRBs would be involved), AAMC favored the recommendation that
sponsors disclose prior IRB judgments to other IRBs.
Proposed Legislation Affecting IRBs. Regarding the issue of IRB
membership, H.R 3594 (108th Congress) contained provisions regarding racial
diversity, scientific expertise, non-scientific expertise, and independence from the
institution. On the topic of racial diversity, the bill would have expanded upon the
Common Rule’s general requirement that IRBs be sufficiently qualified through the
experience and expertise of its members, and the diversity of the members, including
consideration of race, gender, and cultural backgrounds and sensitivity to such issues
as community attitudes, to promote respect for its advice and counsel in safeguarding
the rights and welfare of human subjects. The bill would have directed the HHS
Secretary publish a determination of whether IRBs, when reviewing proposals for
research in which the subjects are primarily minorities, include sufficient numbers
of members from the same minority group. In addition, the Director of OHRP would
have been able to make grants to recruit and train minority individuals to serve on
IRBs. On the topic of the number of IRB members that must have scientific
expertise, H.R. 3594 would have increased the Common Rule’s requirement from at
least one (of at least five members), to the greater of two members or 25 percent of
all members. Similarly, the bill would have increased the Common Rule’s
requirements regarding the number of members who must have non-scientific
expertise and the number who must be otherwise unaffiliated with the institution
from at least one of each, to the greater of at two members or 20 percent of all
members for each category. The bill would have expanded the rule on quorum for
decision-making: quorum would not have been established — and thus the IRB could
not have acted — unless one or more members from each of the above categories
H.R. 3594 (108th Congress) would have addressed the topic of IRB registration,
enhancing OHRP’s requirement for IRB registration (implemented in 2000), by
requiring IRBs to register with the HHS Secretary in a manner and form specified by
the Secretary. The institution served by the IRB would have been required to submit
annually to the Secretary a report that compiles data on the number of new research
proposals reviewed, the number of continuing research projects reviewed, and the
number of reviewed biomedical research proposals.
To facilitate the training of future IRB members, H.R. 3594 (108th Congress)
would have required the institution served by the IRB to ensure that the Board had
Letter from Jordan J. Cohen of the AAMC to FDA, April 8, 2002, at
[http://www.aamc.org/advocacy/library/research/corres/2002/040802.htm], visited Apr. 11,
2005. Note that in April 2005, OHRP sent a letter to University of Washington (UW) in
which findings of noncompliance relative to systemic protections for human subjects were
listed. Letter from Karena Cooper, Compliance Oversight Coordinator, Division of
Compliance Oversight, OHRP, to Mark A. Emmert, President, University of Washington,
Re: Human Research Subject Protections Under Federalwide Assurance FWA-6878 (Apr.
1, 2005). In response, UW’s Vice Provost for Research, Craig Hogan, reportedly said,
among other things, that IRB shopping will end. See Alexander Otto, “Feds Find More
Cause for Concern with uw,” News Tribune [Tacoma, WA], Apr. 20, 2005, p. A1.
an orientation program for new members and a continuing education program for
existing members of the Board. With respect to ethical matters that related to
research, the bill would have required a continuing education program for all
members of the Board. The Common Rule currently has no such requirement.
S. 3060 (107th Congress) would have addressed the topic of weighing risks and
potential benefits by providing specific examples of the types of research considered
to have greater or less than minimal risk to subjects. The Common Rule itself does
not contain examples.96
Mistakes and Misconduct
During the course of clinical research, mistakes and misconduct of researchers,
IRBs, and /or institutions can lead to the injury of human subjects and to the
introduction of ineffective drugs, devices, or biologics into the marketplace. In order
to reduce mistakes and misconduct, recommendations have been made that rules
governing conflicts of interest in research be strengthened; that accreditation be
required for IRBs, researchers and institutions; that smoother protocols be
implemented for reporting adverse events in multisite trials; and that better
provisions be created to monitor ongoing research.
Conflicts of Interest Rules. Conflicts of interest are relationships and/or
arrangements that may inappropriately influence the behavior of investigators,
sponsors and/or IRB members, potentially putting human subjects at risk.
Increasingly, there has been interest in avoiding and/or managing conflicts of interest
in biomedical research, particularly those created by investigators’ and reviewers’
financial ties to institutions whose products are being investigated. The In 2004,
Congress investigated federal agencies’ awards, contracts, and agreements between
employees and outside entities, and paid particular attention to the NIH.97
In February 2005, NIH responded to pressure from Congress and the public
when it announced new, more stringent conflict of interest guidelines for its
employees. The guidelines, which are not a part of 45 CFR 46 or the Common Rule,
generally prohibit NIH employees (a category that does not include grant recipients,
or employees of other agencies that have adopted the Common Rule) from accepting
Note that in 1998, OPRR published some categories of research that may be reviewed
using an expedited procedure if the research also involves less than minimal risk. Categories
of Research That May Be Reviewed by the Institutional Review Board (IRB) through an
Expedited Review Procedure, OHRP, (63 Federal Register 60364-60367 [Nov. 9, 1998], at
[http://www.hhs.gov/ohrp/humansubjects/guidance/63fr60364.htm], visited May 3, 2005.
See, e.g., House Committee on Energy and Commerce, Press Release: Barton,
Greenwood Ask 15 Federal Agencies to Disclose Awards, Contracts and Agreements
B e t w e e n E m ployees and O u t s i d e E n t i t i e s , , J u n . 1 8 , 2 0 0 4 , a t
[http://energycommerce.house.gov/108/News/06182004_1322.htm], visited Apr. 11, 2005;
As a result of the congressional investigation and what FDA “termed ‘a comprehensive
review’ of more than 1800 previously approved requests from its employees to engage in
‘outside activities,’ the United States Food and Drug Administration (FDA) has expanded
the number of scientists and officials required to file confidential financial disclosure
forms.” “FDA Expands Disclosure,” The Scientist, Jun. 21, 2004, at
[http://www.biomedcentral.com/news/20040621/01], visited Apr. 11, 2005.
compensation from or engaging in a range of business dealings with pharmaceutical
and biotechnology companies, supported research institutions, health care providers
and insurers, and related trade, professional or similar associations.98 One provision
of the guidelines has caused some controversy and has reportedly led to difficulty
hiring and maintaining top scientists at NIH.99 The provision, which requires NIH
employees who file public and confidential financial disclosure forms to divest stock
and financial holdings in biomedical companies, and all other employees to have a
maximum of $15,000 in investments, may be reevaluated.100 NIH’s entire conflicts
of interest policy is open to public comment for one year before becoming final.
Another NIH policy, revised in January 2005, articulates restrictions for grant
reviewers that are similar to the new restrictions governing NIH employees (at
[http://grants.nih.gov/grants/peer/COI_Information.pdf]). HHS took action as well,
creating a guidance document to assist IRBs, researchers and institutions with
conflicts of interest related to human subjects research,101 proposing enhancements
to the conflicts rules for applicants and recipients of its funding,102 and calling for
research proposals to foster integrity in research.103
By contrast to NIH, FDA, which already had a rigorous conflict of interest
policy in place for its employees (a category that does not include persons applying
to FDA for product approval), has not proposed recent changes to its policy. The
policy generally prohibits not only FDA employees but also their spouses and minor
children from having financial interest in a significantly regulated organization, such
as a drug company for example. The policy has some exceptions, and also allows for
the possibility of obtaining a waiver in certain circumstances.104 (5 CFR 5501.104)
For an investigator submitting clinical trial data to support an application to market
a product, FDA requires the disclosure or certification information concerning his or
her financial interests if he or she is not an employee of the product’s sponsor. (21
Supplemental Standards of Ethical Conduct and Financial Disclosure Requirements for
Employees of the Department of Health and Human Services, RIN 3209-AA15, 70 Federal
Register 5543, Feb. 3, 2005.
Andrew J. Hawkins, “NIH Stock Divestitures May Have to Be Rethought, Zerhouni
Says”, Washington FAX, Apr. 7, 2005.
Tommy G. Thompson, HHS Secretary, “Financial Relationships and Interests in Research
Involving Human Subjects: Guidance for Human Subject Protection,” HHS Final Guidance
Document, May 5, 2004, at [http://www.hhs.gov/ohrp/humansubjects/finreltn/fguid.pdf],
visited Apr. 7, 2005.
Department of Health and Human Services, “Public Health Service Policies on Research
Misconduct; Proposed Rule,” 69 Federal Register 20777, Apr. 16, 2004.
“Grant Program Initiated Aimed at Understanding Factors That Influence Research
Integrity,” Washington Fax, Aug. 13, 2004.
In addition, FDA’s Commissioner has a permanent five-member Conflict of Interest
Review Board that is to review and make recommendations on all specific or policy matters
relating to certain conflicts of interest arising within the FDA (21 CFR 19.10).
While much of the recent publicity regarding conflicts of interest has been
focused on grant-makers’ and researchers’ financial, institutional and professional
potential biases,105 some similar issues have been raised regarding IRB members’
potential conflicts of interest. The Common Rule and FDA regulations governing
IRB conflicts are identical and preclude any member from participating in reviews
with regard to which the member has conflicting interest, except to provide
information requested by the IRB (45 CFR 46.107(e)(HHS); 21 CFR
56.107(e)(FDA)). Similarly, the HIPAA Privacy Rule prohibits privacy boards from
having any members participating in a review of any project in which the member
has a conflict of interest (45 CFR 45 CFR 164.512(i)(1)(i)). None of the regulations
overtly govern conflicts of interest that researchers or institutions may have, although
the Common Rule and FDA regulations to require an investigator to seek informed
consent only under circumstances that minimize the possibility of coercion or undue
influence, which may be interpreted to preclude such conflict (45 CFR 46.116).106
None of the regulations specify what constitutes a conflict.
In Responsible Research, the IOM recommended that conflicts of interest
reviews for researchers and IRBs be conducted by a distinct body other than the IRB
prior to ethical review. NBAC also addressed the topic, recommending in Human
Participants that Federal policy define institutional, IRB, and investigator conflicts
of interest, and issue guidance to ensure that the rights and welfare of research
participants are protected. NBAC also recommended that all relevant conflicts of
interest be disclosed to participants.
Accreditation of IRBs, Researchers and Institutions. Accreditation is
a procedure by which an authoritative body gives formal recognition that a body or
person is competent to carry out specific tasks. Accreditation may be used in
conjunction with, but is distinct from, both certification (a procedure by which a
disinterested party gives written assurance that a product, process, individual, or
service conforms to specified requirements) and or registration (a procedure by which
a body indicates relevant characteristics of a product, process or service, or
particulars of a body or person, in an appropriate publicly available list). Neither the
Common Rule nor FDA regulations require the accreditation of IRBs, researchers,
or institutions to conduct human subjects research. Likewise, the HIPAA Privacy
Rule does not require accreditation of its privacy boards.
See, e.g., Michelle Mello, et al., “Academic Medical Centers’ Standards for ClinicalTrial Agreements with Industry,” The New England Journal of Medicine, vol. 351, no. 21,
p. 2202 (May 26, 2005).
E.g., “Financial interests are not prohibited, and not all financial interests cause conflicts
of interest or affect the rights and welfare of human subjects. HHS recognizes the
complexity of the relationships between government, academia, industry and others, and
recognizes that these relationships often legitimately include financial relationships.
However, to the extent financial interests may affect the rights and welfare of human
subjects in research, IRBs, institutions, and investigators need to consider what actions
regarding financial interests may be necessary to protect those subjects.” Tommy G.
Thompson, Secretary, HHS, “Financial Relationships and Interests in Research Involving
Human Subjects: Guidance for Human Subject Protection” Financial Guidance Document
(May 5, 2004), at [http://www.hhs.gov/ohrp/humansubjects/finreltn/fguid.pdf].
Though it does not require accreditation, the Common Rule does require each
institution it funds to provide to the governing federal agency a written assurance that
it is complying with the regulations, including those pertaining to the membership
and review procedures of IRBs (45 CFR 46.103(a)). OHRP is to review the
assurances made to HHS (but not to FDA) and determine if the institution is in
compliance. Rarely, OHRP will inspect a facility. FDA may send inspectors to
check on IRBs to ensure compliance with its human subjects regulations during
clinical trials, and has provisions for disqualifying an IRB from participation in
continued or additional research if the IRB fails to meet the regulatory requirements.
Neither the Common Rule nor FDA regulations require the accreditation of
investigators, but if a federal funding agency or the FDA learns that an investigator
is failing to follow human subjects protection requirements (such as those contained
in the Common Rule) the investigator’s federal funding or FDA application may be
terminated. As is the case for compliance with IRB regulations, the Common Rule
requires institutional assurances of compliance with investigator regulations. OHRP
is to review the assurances and may inspect facilities. Likewise, FDA may also
inspect facilities to ensure compliance.
For investigators, both the Common Rule and FDA regulations require them to
maintain and report to IRBs specific types of documentation related to the protection
of human subjects. The HIPAA Privacy Rule requires the same with respect to its
privacy boards. In addition, since October 2000, NIH has required that all
investigators submitting NIH applications for research grants involving human
subjects be educat ed about human subjects protection (at
education requirement means that researchers will have successfully completed a
short course. It does not mean that their processes for human subjects protections
have been reviewed and accredited.
Several groups have made recommendations for accreditation of institutions that
conduct human subjects research, investigators, and IRBs. In 2000, following an
April 1999 announcement from the Under Secretary for Health of the Veterans
Health Administration (VHA), the VHA engaged an external contractor, the National
Committee for Quality Assurance (NCQA),107 to inspect and certify the human
subjects protection program of every VA facility conducting research involving
human subjects (Veterans Affairs Medical Centers - VAMCs).108 In 2001, NCQA
and VHA launched the first ever accreditation program for human research
NCQA is an independent, 501(c)(3) non-profit organization whose mission is to improve
health care quality everywhere. Information about its VA Human Research Protection
Accreditation Program (VAHRPAP) can be found at
[http://www.ncqa.org/Programs/QSG/VAHRPAP/vahrpap.htm], visited July 12, 2005.
Testimony of Thomas L. Garthwaite, M.D,, Under Secretary for Health, Department of
Veterans Affairs, on the Protection of Human Subjects of Research in the Veterans Health
Administration, before the Subcommittee on Oversight and Investigations of the Committee
on Veterans’ Affairs, U.S. House of Representatives (Sept. 28, 2000), at
[http://veterans.house.gov/hearings/schedule106/sept00/9-28-00/tgarthwa.htm], visited May
protection.109 NCQA reportedly conducted accreditation visits to 23 facilities — 20
of which were accredited with conditions,110 two of which were not accredited, and
one of which withdrew from the process.111 As of July 12, 2005, NCQA listed 42
VAMCs as accredited, 13 as having pending accreditation of their academic affiliate,
and one as deferred.112 According to the VA’s Office of Research Oversight,
approximately 117 VAMCs conduct human subjects research.113 The VA reportedly
expects accreditation of all VAMC facilities to be completed by the summer of
In 2001, the IOM and the NBAC each recommended implementing an
accreditation program for research institutions as one possible tool for strengthening
the current system.115 In 2002, IOM recommended in Responsible Research that, in
addition, research sponsors develop criteria for evaluating the performance and
enhancing the practice of quality improvement, and that institutions have written
policies and procedures that detail internal auditing and oversight processes. Some
in industry oppose measures like accreditation that might increase the cost of
research.116 Others claim that the resulting good practice and proper conduct in
“NCQA, VA Launch First Ever Accreditation Program for Human Research Protection,”
NCQA News, (Aug. 28, 2001), at [http://www.ncqa.org/communications/news/vahrpap
launch.htm], visited May 3, 2005.
“A facility accredited with conditions met most of the accreditation standards.”Testimony
of Cynthia A. Bascetta, Director, Health Care, Veteran’s Health Benefits Issues, on VA
Research: Actions Insufficient to Further Strengthen Human Subjects Protections before the
Subcommittee on Oversight and Investigations, Committee on Veteran’s Affairs, House of
Representatives (Jun. 18, 2003), at [http://veterans.house.gov/hearings/
“Veteran’s Affairs Human Research Protection Accreditation Program Status List,”
NCQA, (July 1, 2005), at [http://www.ncqa.org/Programs/QSG/VAHRPAP/VA%20Status
%20List.pdf], visited July 12, 2005.
Telephone conversation with Peter N. Poon, JD, MA, Health Science Specialist, Office
of Research Oversight, VA (202) 565-8107, on May 9, 2005.
Testimony of Cynthia A. Bascetta, Director, Health Care, Veteran’s Health Benefits
Issues, on VA Research: Actions Insufficient to Further Strengthen Human Subjects
Protections before the Subcommittee on Oversight and Investigations, Committee on
Veteran’s Affairs, House of Representatives (Jun. 18, 2003), at
IOM, Preserving Public Trust: Accreditation and Human Research Participant
Protection Programs (Washington, DC: National Academy Press, Apr. 2001); NBAC,
Ethical and Policy Issues in Research Involving Human Participants, Aug. 2001, p. 11.
According to the 2005 fee schedule for the Association for the Accreditation of Human
Research Protection Programs, Inc. (an organization that accredits IRBs and institutions)
the cost of accreditation varies with the number of protocols it reviews annually, rising as
the number of protocols increases. For example, for an IRB or an institution with an IRB
that reviews less than 100 protocols per year, the application fee is $8,100 and the annual
fee is $4,400 thereafter. For 2,501-3,000 protocols per year, the application fee is $26,600,
research would pay off both scientifically and economically; the problems that flow
from poorly conducted human subjects research may call results into question, and
may cause harm to the subjects, leading to medical expenses and possibly to
litigation and a loss of investor confidence.117
In a July 2004 letter to the HHS Secretary, SACHRP recommended the
voluntary accreditation of IRBs.118 Two programs provide voluntary accreditation
for IRBs and for institutions involved in human subjects research: the Partnership for
Human Research Protection, Inc. (PHRP - which was formed by NCQA) and the
Association for the Accreditation of Human Research Protection Programs, Inc.
(AAHRPP). According to the AAHRPP and PHRP websites, as of July 11, 2005, a
combined total of 23 institutions and eight IRBs had been accredited, and two
institutions had received a qualified accreditation.119 AAHRPP and PHRP keep the
accreditation process confidential, so the number of accreditation applicants is not
published.120 SACHRP’s July 2004 letter also expressed concern that the cost and
scope of the accreditation process may be impediments for some institutions to seek
accreditation. However, SACHRP also added that natural market pressures would
push institutions toward seeking accreditation.
Adverse Event Reporting and Multisite Research. An adverse event
(AE) is an unfavorable medical occurrence in subjects exposed to drugs, biologics,
or medical devices. For example, an AE may be nausea, dry mouth, anxiety, or even
death. Adverse event reporting (AER) is the process of disseminating information
about individual AEs to the principal investigators and IRBs, and where appropriate,
to regulatory agencies and consumers. In the event that the principal investigator
determines that an AE constitutes a new or previously unidentified risk, the informed
consent form may need to be revised to reflect the new risk. Any consent revisions
must be submitted to the IRB along with the adverse event information. If the IRB
and the annual fee is $11,000 thereafter. “Fees,” Association for the Accreditation of
Human Research Protection Programs, Inc., at [http://www.aahrpp.org/www.aspx?Page
ID=17], visited Apr. 11, 2005.
William Alexander, et al., “Realities at the leading edge of research,” EMBO Reports,
vol. 5, no. 4 (2004), p. 324.
Letter from Ernest D. Prentice to Secretary Thompson, July 8, 2004, at [http://www.hhs.
gov/ohrp/sachrp/pages3-7from08112004sec.pdf], visited July 11, 2005.
Note that both AAHRPP and PHRP list a review of an institution’s IRB as one
component of institutional accreditation. AAHRPP lists 19 organizations and four IRBs that
they have accredited, and one organization with a qualified accreditation. PHRP lists four
organizations and five IRBs they have accredited. One IRB (Chesapeake Research Review,
Inc.) is accredited by both organizations. [http://www.aahrpp.org/www.aspx?PageID=
11$1$100]; [http://www.phrp.org/show.asp?durki=6856], both visited July 11, 2005.
“Because the accreditation process is confidential, AAHRPP does not release information
about applicants that are in the process of seeking accreditation or those that have been
placed in the Accreditation-Pending or Accreditation Withheld categories.” Accredited
Organizations, AAHRPP, at [http://www.aahrpp.org/www.aspx?PageID=11$1$100], visited
May 3, 2005. See also, “Confidential Information” in Public Policy Information, PHRP, at
[http://www.phrp.org/show.asp?durki=6720&site=54&return=4819], visited May 3, 2005.
determines there is an increased risk to subjects based on the adverse event reports,
the research may be suspended.
Both HHS’s Common Rule and the FDA’s regulations have provisions that
apply to AER. (HIPAA’s Privacy Rule, which is focused on protecting information
rather than patient safety, contains no provisions regarding AEs or AER, except by
reference to FDA regulations (45 CFR 164.512(b)(1)(iii)(A)). The Common Rule
requires institutions that receive federal funding to assure their funders that they have
written procedures for AER. Procedures must require reporting to the IRB,
appropriate institutional officials, and the department or agency head of any
unanticipated problems involving risks to subjects (45 C.F.R. 46.103(b)(5)). The
Common Rule does not specify who is or should be made responsible for reporting
this information to the IRB. The FDA has parallel (although not identical)
requirements. (21 CFR 56.108(b)).121
Recent public discussions regarding problems with AER requirements have
focused the interaction of the Common Rule’s requirements with a separate set of
FDA regulations — those governing Investigational New Drug Applications (INDs),
which sponsors submit to obtain FDA permission for clinical trials to test new drugs.
FDA’s IND regulations require a researcher to inform the sponsor if a drug effect is
adverse (21 CFR 312.64(b)), and to the IRB if a problem involving risk to human
subjects is unanticipated (21 CFR 312.66). Alone, these regulations may be in
harmony with the Common Rule. However, the IND regulations also require the
sponsor to notify FDA and all participating investigators of an adverse experience
associated with the use of the drug if it is both serious and unexpected (21 CFR
312.32(c)(1)(i)(A)). When applied to multicenter trials (in which multiple
investigators and IRBs may be involved), this serious and unexpected threshold,
when contrasted with the Common Rule’s unanticipated threshold has caused
confusion for investigators, sponsors, and IRBs in two points. First, when an
unanticipated but not serious AE occurs at one research site, must all of the IRBs in
the study — or perhaps one centralized IRB — be informed, and by whom? Second,
who is responsible for determining whether an AE is serious — a researcher, sponsor,
Questions that do not focus on the differences between the Common Rule’s and
FDA’s regulatory requirements have also been raised. Even if dealing with a single
set of regulations, the AER process has been described as unwieldy for some research
conducted at multiple locations, and therefore with many investigators and IRBs.
The Common Rule specifies that, in multi-site research, each institution is
responsible for safeguarding the rights and welfare of human subjects at its location,
though the Rule does provide that a Department or Agency head may approve a joint
review arrangement that allows one IRB to rely upon the review of another qualified
IRB to avoid duplication of effort (45 CFR 46.114). By contrast, FDA regulations
allow for joint review without requiring approval from a Department or Agency head
The one distinction between the Common Rule at 46.103(b) and the FDA regulations at
56.108(b) is that FDA requires IRBs to follow written procedures for reporting to the IRB,
appropriate institutional officials, and the Food and Drug Administration, where the
Common Rule requires reporting to the department or agency head.
(21 CFR 56.114).122 Given that each institution is responsible for protecting subjects
at its location, it may make sense for all AERs to be shared among all relevant
personnel and IRBs. On the other hand, the IRB of a major research institution with
scores of researchers, each playing large and small roles in multiple protocols, may
be inundated with AERs, many of which may not be relevant to the portion of the
research being conducted at the IRBs’s location.123
In March 2005, the FDA issued a draft Guidance for Industry — Using a
Centralized IRB Process in Multicenter Clinical Trials,124 which was preceded by a
public meeting to discuss AER during multi-site trials.125 Some groups suggested
that it would help IRBs to manage their workload if sponsors and investigators were
able to decide which AEs merited reporting to the IRB.126 Others criticized the
suggestion, stressing that the primary purpose of IRBs is to protect research subjects
and recommending that measures be taken to further insure independence of IRBs
from both sponsors and parent institutions who may have conflicts of interest with
regard to determining what constitutes an AE.127
On May 27, 2005, OHRP issued guidance on procedures institutions may use
to file incident reports, which include AERs, serious or continuing noncompliance
with 45 CFR part 46 or the requirements or determinations of the IRB, and
In Mar., 2005, FDA made available for comment a draft guidance document to assist
sponsors, institutions, institutional review boards (IRBs), and clinical investigators involved
in multicenter clinical research in meeting the requirements of 21 CFR part 56 by facilitating
the use of a centralized IRB review process: Using a Centralized IRB Review Process in
Multicenter Clinical Trials, Mar. 2005 at [http://www.fda.gov/cder/guidance/OC273.htm],
visited May 3, 2005.
For example, one major research center (Washington University in St. Louis, MO) had
over 11,000 AERs delivered to its IRB in 2003. Patricia Scannell, “Using Technology to
Strengthen Human Subject Protections,” presented at the Fourth National Medical Research
Summit, Baltimore, MD, Apr. 2004.
Available from FDA at [http://www.fda.gov/cder/guidance/OC273.htm], visited May 3,
FDA, HHS, “Reporting of Adverse Events to Institutional Review Boards; Public
Hearing” Public Hearing Notice [Docket No. 2005N — 0038], 70 Federal Register 6693
(Feb. 8, 2005).
See, e.g., Yvonne K. Higgins, Associate Director, Office of Regulatory Affairs,
University of Pennsylvania, “PENN’s Response to Managing Adverse Event Reports,”
presentation at FDA’s public meeting on Reporting of Adverse Events to Institutional
Review Boards, March 21, 2005. The most recent comments on FDA’s meeting can be
found on the FDA Dockets website [Docket number 2005N-0038] at
[http://www.fda.gov/ohrms/dockets/dockets/05n0038/mostrecent.htm], visited Apr. 11,
See, e.g., “Statement of Michael Susko,” President, Citizens for Responsible Care and
Research, presented to FDA’s Reporting of Adverse Events to Institutional Review Boards,
March 21, 2005. The most recent comments on FDA’s meeting can be found on the FDA
Dockets website (Docket number 2005N-0038) at [http://www.fda.gov/ohrms/
dockets/dockets/05n0038/mostrecent.htm], visited Apr. 7, 2005.
suspension or termination of IRB approval.128 The guidance focused on the following
topics: (1) Applicability of incident reporting requirements; (2) information to be
included in incident reports; (3) time frame for reporting incidents; (4) OHRP focus
on corrective actions when reviewing incident reports; and (5) OHRP’s response to
Several groups had considered the issue of AER and made recommendations on
the topic prior to OHRP’s and FDA’s issuance of guidance documents. Following
numerous discussions on the topic, SACHRP wrote a letter to Secretary Thompson
recommending that OHRP and FDA “promptly issue clear and consistent joint
guidance on IRB review of both internal and external AERs which will best serve to
protect human subjects and effectively reduce regulatory burden.”129
NBAC addressed AERs in Human Participants, recommending that the federal
government create a uniform system for reporting and evaluating adverse events
occurring in research, especially in multi-site research, clarifying the reporting and
evaluation responsibilities of investigators, sponsors, IRBs, Data and Safety
Monitoring Boards,130 and federal agencies. NBAC further recommended that for
multi-site research, federal policy should permit central or lead IRB review, rather
than the common practice of review by multiple IRBs at multiple sites.
IOM looked more broadly at issues involved with multicenter trials in its report,
Responsible Research. It recommended that research organizations, sponsors, and
IRBs streamline the reviews and processes in multisite trials by assigning a lead
review committee for each trial. This assignment could resolve issues involved with
AER as well as those related to the lack of consistency in the levels of review among
Informed Consent. While it is generally accepted that meaningful informed
consent is an essential component of human subjects protections, some questions
have been raised regarding whether the informed consent requirements of the
Common Rule (and the identical FDA informed consent requirements)131 could be
OHRP, “Guidance on Reporting Incidents to OHRP,” (May 27, 2005), at [http://www.
hhs.gov/ohrp/policy/incidreport_ohrp.html], visited July 11, 2005.
Letter from Ernest D. Prentice to Secretary Thompson, July 8, 2004, at [http://www.hhs.
gov/ohrp/sachrp/pages3-7from08112004sec.pdf], visited July 11, 2005.
A Data and Safety Monitoring Board (DSMB) is an entity distinct from an IRB that
conducts and reports to the sponsor the results of (1) reviews of accumulating clinical data
relating to the efficacy and safety of the investigational product (drug, biologic and/or
device); (2) interim analyses of the clinical data to determine whether the study needs to be
terminated for safety reasons; and (3) evaluations of the continued scientific validity and
merit of the study. DSMB review is required by some federal sponsors for some research
See, e.g., “NIH Policy for Data and Safety Monitoring,” June 10, 1998, at
[http://grants.nih.gov/grants/guide/notice-files/not98-084.html], visited Apr. 11, 2005.
The content of 45 CFR 46.116 (the Common Rule’s informed consent requirements) is
identical to 21 CFR 50.25 (the FDA regulation’s informed consent requirements).
improved.132 For example, the Common Rule’s emphasis on informed consent
documentation has sparked some inquiry into whether the Rule’s requirements —
that a person read and sign a form — actually result in subjects’ understanding the
research so that they can meaningfully agree to participate. Some investigators have
found that tools such as documents tailored to low-level readers, culturally
appropriate visual aids, and interactive process are helpful in ensuring that potential
subjects not only receive, but also understand the information that they need in order
to decide whether to participate in a research study.133
In order to ensure that consent is achieved and documented, IOM recommended
in Responsible Research, that the informed consent process consist of a dynamic,
ongoing, interactive dialogue between staff and research participants. To distinguish
the legal documentation from the interactive process, the IOM recommended that
forms signed to provide legally valid consent be called consent forms rather than
informed consent forms. IOM stressed that IRBs should ensure that the focus of the
informed consent process and the consent form is on informing and protecting
participants, NOT on protecting institutions. Further, the protection program should
be transparent and open to the public.
The NBAC made similar recommendations in Human Participants, suggesting
that Federal policy emphasize the process of informed consent rather than the
documentation and ensure that competent participants have given their voluntary
informed consent. NBAC also recommended issuing guidance about how to provide
information to prospective subjects, how to promote their comprehension, and how
to ensure that they continue to make informed and voluntary decisions.
Monitoring of Ongoing Research. While much of the focus of the federal
human subjects protection regulations falls on review prior to the start of research,
some provisions also deal with the appropriate way to monitor ongoing research.
The Common Rule and FDA regulations each require IRBs to have written
procedures that specify how they will conduct continuing review of ongoing research.
(The HIPAA Privacy Rule has no parallel provision.) The reviews should be
conducted at intervals appropriate to the degree of risk, but not less than once per
year (45 CFR 46.103(b)(4), 109(e) (HHS); 21 CFR 56.109(f) (FDA)). However,
other than granting IRBs the authority to observe (or have a third party observe) the
consent process and the research, the regulations do not specify how the ongoing
review should occur.
In Human Participants, NBAC found that continual review and oversight of
ongoing research are necessary to ensure that emerging data or evidence have not
The HIPAA Privacy Rule does not require informed consent, but rather requires
researchers to obtain an authorization from those whose information is used. (For more
information about the authorization process and its interaction with informed consent, see
the HIPAA Privacy Rule section in Appendix A of this report.)
See, e.g., D. R. Young, D.T. Hooker, and F.E. Freeberg. “Informed Consent Documents:
Increasing Comprehension by Reducing Reading Level.” IRB: A Review of Human Subjects
Research vol. 12, no. 3, 1990; NBAC, Ethical and Policy Issues in Research Involving
Human Participants, Aug. 2001, p. 100.
altered the risks/potential benefits assessment to make the risks no longer reasonable.
Therefore, NBAC recommended that federal policy be developed to describe how
sponsors, institutions, IRBs and investigators should monitor ongoing research.
NBAC advised that continuing review was not necessary for studies involving
minimal risk, research involving the use of existing data, or research that is in the
data analysis phase when there is no additional contact with participants. However,
when continuing review was not required, NBAC recommended that other
mechanisms be in place for ensuring the compliance of investigators and for
reporting protocol changes or unanticipated problems encountered in the research.
Proposed Legislation Affecting the Prevention of Mistakes and
Misconduct. On the topic of adverse event reporting, H.R. 870 (109th Congress)
would create criminal penalties for drug manufacturers’ chief executives and/or other
members of the senior executive management group who knowingly conceal reports
of serious adverse drug experiences related to drugs for which the manufacturer was
seeking or had received FDA approval for marketing. An executive found to have
violated the act would incur fines of not more than $2,000,000, a prison term of a
minimum of 20 years to life, or both. The act would also prohibit a company from
indemnifying any person found to have violated its provisions.
On the topic of conflicts of interest, H.R. 3594 (108th Congress) would have
required the HHS Secretary to review the Common Rule and other applicable
regulations not later than 18 months after the enactment of the act addressing (among
other things) issues related to significant financial interest, and attestations by clinical
investigators regarding the protection of human subjects. In addition, H.R. 3594
would have required IRB members to disclose significant financial interests, and to
have recused themselves from reviewing proposals in which they had a significant
conflict or interest. Investigators would have been required to disclose to IRBs any
significant conflicts of interest related to the research, any previous disqualifications
or restrictions by any Federal entity in their ability to conduct human subject
research, and any previous IRB reviews. The institution served by the IRB would
have also had to review the potential investigators’ conflicts of interest, and have
sought to manage, reduce, or eliminate such conflicts.
On the topic of IRB accreditation, H.R. 3594 (108th Congress) would have given
the HHS Secretary the authority to recognize a private accrediting entity or entities,
and to facilitate but not to require IRB accreditation.
For research projects involving multiple locations, H.R. 3594 (108th Congress)
would have enabled the requirements of the Common Rule to be met by a single lead
IRB. A principal investigator would have had to report AEs to the lead IRB (not
necessarily to all IRBs) and the sponsor, in a timely manner appropriate to the
severity and unexpectedness of the event.
On the topic of monitoring ongoing research, H.R. 3594 (108th Congress) would
have enabled IRBs to report regulatory non-compliance to the HHS Secretary. The
bill would have also required the Director of OHRP to provide advice to institutions
regarding compliance with the Common Rule and improvements in human subjects
protections. The Director would have been able to conduct audits to ensure
compliance with the Common Rule, and offer corrective action and/or impose
S. 3060 (107th Congress) would have required that all IRBs be accredited by the
Director of ORHP within six years. The basis for accreditation would have been
evaluated in terms of: the expertise of the members, adequacy of the members’
education on principles and procedures of human research participant protections,
whether decisions were insulated from financial conflicts of interest, whether
research was reviewed in accordance with ethical principles, the informed consent
process and the presence of research monitoring practices.
With regard to financial conflicts of interest, S. 3060 (107th Congress) would
have required disclosure of potential conflicts of investigators and IRB members to
the IRB or a conflict of interest committee. If the IRB granted a waiver for an
investigator with such conflicts to participate in research, the investigator would have
had to disclose the financial interest to participants in the research as part of the
informed consent process. If a waiver was granted, the IRB could have required
additional safeguards, including audits of the informed consent process, third party
monitoring of the consent process, establishment of a data and safety monitoring
board, requiring the investigator to hold financial interests in escrow prior to
conducting the research or other measures as the IRB determined reasonable and
necessary to protect participants. In addition, S. 3060 would have required
investigators and sponsors to disclose any financial conflicts of interest to editors and
publishers of peer-reviewed publications or other media.
Although S. 3060 (107th Congress) would have imposed no new informed
consent requirements, it did have provisions for the Director to promulgate
regulations regarding payment for recruiting or participation of the human subjects.
S. 3060 also would have required the Director to promulgate regulations regarding
the appropriate use of placebo or non-treatment in clinical studies.
Injuries and Medical Care
As a result of their participation in clinical research human subjects may sustain
injuries, and may require routine and/or emergency medical care. The Common
Rule and FDA regulations (and the HIPAA Privacy Rule by reference) require that
the informed consent document contain an explanation of any additional costs that
the subject may incur as a result from participation in the research (45 CFR
46.116(b)(3) (HHS); 21 CFR 50.25(b)(3) (FDA). They also require that, for research
involving more than minimal risk, the informed consent document must contain an
explanation as to whether any compensation and medical treatments are available if
injury occurs and, if so, what they consist of, or where further information may be
obtained (45 CFR 46.116(a)(6)(HHS); 21 CFR 50.25(a)(6)). However, neither the
Common Rule nor the FDA regulations specify if or when it is appropriate for IRBs,
sponsors, or investigators to compensate subjects for the cost of their additional
medical care or for research-related injuries.134
Since 1998, the Department of Veterans Affairs has required VA medical facilities to
The Common Rule and FDA regulations also prohibit the inclusion of
exculpatory language (through which the subject or the representative is made to
waive or appear to waive any of the subject’s legal rights, or releases or appears to
release the investigator, the sponsor, the institution or its agents from liability for
negligence) in the informed consent document (45 CFR 46.116 (HHS); 21 CFR
50.20 (FDA)). This prohibition may suggest that such liability could flow from
research. However, neither the Common Rule nor the FDA regulations prohibit
sponsors, investigators, or others from asking subjects to sign documents that are
unrelated to informed consent and contain exculpatory language.
Questions have been raised regarding who should bear the cost of subjects’
medical care, and whether IRBs should be held legally liable for allowing a study that
harmed a subject to take place. The following sections describe the debate and
proposed legislation on these topics. There is no proposed legislation section at the
end of the injuries and medical care section because legislation introduced in recent
Congresses related to the Common Rule and protection of human research subjects
would not have affected changes in this area; however relevant changes to Medicare
and Medicaid laws are discussed in the cost of medical care section that follows.
Cost of Medical Care During Human Subjects Research and
Compensation for Research-Related Injuries.When a person participates in
research, the cost of tests, procedures, drugs and any research activity directly
associated with the investigation, are typically covered by the group sponsoring the
research, such as a pharmaceutical company or the NIH. On the other hand, the cost
of routine patient care, which would typically be covered by the individual’s health
insurance plan if he or she were not enrolled in a study, may not be covered by the
sponsor. These costs may also be excluded from insurance coverage, because some
insurance providers define research and the related required medical services as
investigational or experimental. Study participants may thus incur out-of-pocket
costs for services such as such as the doctor visits, hospital stays, diagnostic tests and
x-rays, that they would normally receive if not enrolled in a trial.135
In 2000, Medicare began covering the patient care costs of beneficiaries in some
clinical trials.136 While many state Medicaid programs have no legal requirements
provide necessary medical treatment to research subjects injured as a result of participation
in research projects approved by a VA Research and Development Committee and
conducted under the supervision of one or more VA employees. (38 CFR 17.85, published
at 63 Federal Register 11123 [Mar. 6, 1998])
National Conference of State Legislatures (NCSL), “Clinical Trials: What Are States
Doing? 2004 Update,” 2003, at [http://www.ncsl.org/programs/health/2004clinical
trials.htm], visited Apr. 12, 2005.
“On Jun. 7, 2000, the President issued an executive memorandum directing the Centers
for Medicare & Medicaid Services (CMS) to “explicitly authorize [Medicare] payment for
to cover clinical trials costs, many do cover all or some of the costs. In addition, a
growing number of states have passed legislation or instituted special agreements
requiring health plans to pay the cost of the routine medical care a patient receives
as a participant in a clinical trial.137
IRB Liability for Research-Related Injury. In the course of human
subjects research, IRBs are responsible for reviewing protocols, in part to assure that
proper informed consent is obtained and that the human subjects are properly
protected. In certain circumstances, persons harmed during research studies have
sought to sue IRBs, in addition to investigators and sponsors. SACHRP heard a
report about the current legal trends, potential sources of legal immunity for IRBs,
and touched on the issue of whether subjects should be allowed to sue IRBs.138
Proponents of litigation stressed the following:
the tort system presents a good way to punish harm doers, or those
who are negligent in their responsibilities;
the threat of litigation motivates IRBs to adhere to best practices;
litigation itself gives people who suffer harms as a result of their
participation in research a venue to hold accountable those
responsible for ensuring an appropriate balance of risks and benefits
and an appropriate informed consent process.
Opponents of litigation noted that obtaining information about litigation trends
was difficult because of the lack of a centralized information source and a tendency
of parties to settle rather than litigate. However, they expressed some concern that
litigation, or the fear of it, might have the following effects:
routine patient care costs...and costs due to medical complications associated with
participation in clinical trials.” In keeping with the President’s directive, this National
Coverage Decision (NCD) serves to define the routine costs of clinical trials and identify
the clinical trials for which payment for such routine costs should be made for eligible
services furnished on or after Sept. 19, 2000. Centers for Medicare and Medicaid Services,
Medical Coverage — Clinical Trials, Provider Bulletin, at [http://www.cms.hhs.gov/
coverage/8d4.asp], visited Apr. 11, 2005.
The following states have passed legislation requiring some degree of medical coverage
for those who participate in certain clinical trials: Arizona, California, Connecticut,
Delaware, Georgia, Illinois, Louisiana, Maryland, Maine, Massachusetts, Missouri, New
Hampshire, Nevada, New Mexico, North Carolina, Rhode Island, Vermont, Virginia, and
West Virginia. The following states have special agreements with insurance companies to
voluntarily provide coverage for clinical trials; Georgia, Michigan, New Jersey, and Ohio.
NCSL, Clinical Trials: What Are States Doing? 2004 Udpate, 2003, at [http://www.ncsl.org/
programs/health/2004clinicaltrials.htm], visited Apr. 11, 2005.
E. Haavi Morreim, “Litigation in Clinical Research: Problems and Solutions,” presented
to SACHRP, Alexandria, VA, April 2004 at [http://www.hhs.gov/ohrp/sachrp/mtgings/
mtg03-04/morriem_files/frame.htm], visited Apr. 11, 2005.
increased difficulty finding people to serve on IRBs (IRB members
are generally unpaid);
longer, more complex informed consent forms (informed consent
forms may not contain exculpatory language, and they may create
liability if they do not communicate the risks appropriately);
unwieldy levels of adverse event reporting (discussed below) and
inhibition of research;
increased cost of research for sponsors, including government, via
higher indirect costs to cover liability insurance; and
difficulty obtaining institutional and independent insurance.
SACHRP recommended that the report be transmitted to the IOM, and that no
further action be taken on the subject.
NBAC looked into the issue of research-related injuries, recommending in
Human Participants that the federal government study the issue to determine if there
is a need for a compensation program. As an alternative to litigation related to
research, IOM’s Responsible Research contained the recommendation that a no-fault
compensation system be set up to compensate any research participant who is injured
as a direct result of participating in research, without regard to fault. Compensation
should include at least the costs of medical care and rehabilitation. Rather than
focusing on litigation against IRBs, IOM’s proposals focused on compensating
subjects for physical harm and avoiding litigation against sponsors and investigators.
This may also eliminate the need for lawsuits against IRBs by compensating subjects
without requiring that they prove others’ wrongdoing.
The Future of Human Subjects Research Protections
The Common Rule does not contain language regarding how the system of
human research protections can be reassessed, modified, or funded. Nevertheless,
continued experience with human subjects regulations and the changing scope of the
research protocols themselves can spark insights that may improve the regulatory
system. Questions have arisen regarding whether there is a need to reassess the
system periodically, what resources may be necessary to ensure the efficacy of the
system, and what burdens and benefits may flow from regulatory changes. The
following sections describe the debate and proposed legislation on these topics.
Periodic Reassessment. Given the breadth and complexity of the issues
that arise in research involving human beings, some groups have called for an
ongoing process for reassessing the regulations and their impact. To provide
policy-makers with ongoing input and advice, in Responsible Research, IOM
recommended the establishment of a nonpartisan, independent body of experts to
ensure that the national protection system receives objective public advice. The body
would consist of balanced representation of the perspectives of participants, a range
of scientific disciplines, bioethics, and IRB experts. NBAC, as well, had
recommended in Human Participants, that the federal government, in partnership
with academic institutions and professional societies facilitate discussion about
emerging human research protection issues and develop a research agenda that
addresses issues related to research ethics.
Additional Resources. In order to prioritize the protection of human
participants in research, NBAC stressed the need for adequate resources in addition
to those required by the Common Rule (i.e., adequate meeting space and sufficient
staff support for recordkeeping) (45 CFR 46.103(b)(2)). In Human Participants,
NBAC called for the appropriation of funds to carry out the functions of NBAC’s
proposed federal oversight office. NBAC also recommended that federal
appropriations for research programs include a separate allocation for oversight
activities related to the protection of human participants, that institutions be
permitted to request grant funding for IRBs and other oversight activities, and that
federal agencies, other sponsors, and institutions make additional funds available for
a range of oversight activities. The NBAC proposal regarding grant funding
addressed, in part, NIH policy regarding grantees’ ability to recover costs associated
with IRB approval. According to the current policy, IRB costs139 are not recoverable
as direct expenses (they are considered to be a part of overhead), unless such costs
are not included in the institution’s facilities and administrative rate.140
Regulatory Change. In Responsible Research, the IOM questioned the
clarity and relevancy of the Common Rule. While the HHS Secretary could modify
the language of the Common Rule or 45 CFR 46, making changes to the Common
Rule itself would be a logistically complex undertaking for HHS. Not only would
HHS have to amend its own regulations (a time consuming activity in and of itself),
but to keep the Common Rule “common” among the signatory agencies, HHS may
also need to lead a lobbying effort to convince each of the federal agencies that
follows the Common Rule to adopt the amendment. For this reason, in Responsible
Research, IOM proposed that Congress, rather than HHS, take the necessary steps
to broaden and strengthen the federal oversight system and to make appropriate
Common Rule modifications as needed.
Other commentators have expressed reservations about the introduction of new
regulations. Some objections are based upon regulations’ potential to increase the
cost of bringing new drugs to market.141 The average cost of developing a new
prescription medicine was estimated to be $400 million - $800 million in 2001, and
rapidly increasing.142 Another set of objections have focused on the effect that
By one estimate, IRB activities cost each U.S. academic medical center $170,000 to $5
million per year. Jeremy Sugarman, et al., “The Cost of Institutional Review Boards in
Academic Medical Centers,” New England Journal of Medicine, vol. 352, no. 17 (Apr.
2005), p. 1825.
“NIH Policy on Direct Cost Charges for IRB Review,” NIH [NOT-OD-03-042], May 22,
2003, at [http://grants2.nih.gov/grants/guide/notice-files/NOT-OD-03-042.html], visited
Apr. 11, 2005.
See, e.g., Gillian A. Hood, “A Perspective from One Clinical Research Center in the
United Kingdom,” Applied Clinical Trials, (May 1, 2004), at [http://www.actmagazine.com/
appliedclinicaltrials/article/articleDetail.jsp?id=94508], visited Apr. 11, 2005.
See, e.g., “Tufts Center for the Study of Drug Development Pegs Cost of a New
Prescription Medicine at $802 Million,” Tufts University News Release (Nov. 30, 2001), at
[http://csdd.tufts.edu/NewsEvents/RecentNews.asp?newsid=6], visited Apr. 11, 2005; and
Kevin Davies, “Counting the Cost of Drug Discovery,” Bio IT World (July 11, 2002), at
regulations have on the timing of bringing a drug to market, and the resulting loss of
life that may result from regulatory delays.143 These concerns have led some to urge
caution when considering the implementation of new regulations governing clinical
Proposed Legislation Affecting Future Human Subjects
Protections. H.R. 3594 (108th Congress) would have required each institution
served by an IRB to annually submit to the Secretary a report that compiles data on
the number of new research proposals reviewed, the number of continuing research
projects reviewed, the number of reviewed biomedical research proposals, the
number of reviewed behavioral or social sciences research proposals, and any
additional information determined appropriate by the Secretary. In addition, the
Secretary may have required an institution to submit such reports regarding the IRB
as the Secretary determined to be appropriate. The bill would have also enabled the
HHS Secretary to permit individual Federal agencies to create additional protections
for human subjects research that they fund or conduct.
H.R. 3594 (108th Congress) would have authorized the appropriation of
$20,000,000 for FY2004 for OHRP to carry out its compliance and enforcement
responsibilities, and for its Director to carry out certain responsibilities related to
protecting human subjects. Further, the bill would have allowed institutions to
recover costs associated with compliance for human subject protections under this
part from government sponsors of research as direct costs. In addition, the OHRP
Director would have been able to make grants for the development of a model
education program to be used by institutions served by IRBs, as well as to facilitate
minority recruitment on IRBs. The bill would have authorized to be appropriated
such sums as may have been necessary to support the model education program.
S. 3060 (107th Congress) would have addressed the topic of funding for human
subjects protections and regulatory change by authorizing the appropriation of
$20,000,000 to establish the National Office of Human Research Protections, and to
develop standards of practice. It would have also authorized the appropriation of
$15,000,000 for demonstration grants to improve IRB function, and other sums as
necessary to have carried out the act.
See, e.g., Dale H. Gieringer, “Compassion vs Control: FDA Investigational-Drug
Regulation,” Cato Policy Analysis, no. 72, (May 20, 1986), describing the loss of life from
delayed clinical trials and limited access to AIDS drugs, at [http://www.cato.org/pubs/
pas/pa072.html], visited Apr. 11, 2005.
Appendix A: The Common Rule’s (and 45 CFR 46’s)
Interaction with FDA Regulations
and the HIPAA Privacy Rule
A variety of regulations can impact the conduct of human subjects research. As
discussed in previous sections, these include not only the Common Rule and other
parts of 45 CFR 46, but also the HIPAA Privacy Rule (45 CFR 164), and FDA
regulations (21 CFR 50, 56). Conversations have arisen regarding how best to
protect human subjects in light of the sometimes conflicting requirements of the
various regulations. The information in this appendix summarizes the debate and
proposed legislation focused on the interaction of the Privacy Rule and the FDA
regulations with the Common Rule and some other portions of 45 CFR 46.
The HIPAA Privacy Rule
The Privacy Rule established a set of national standards for the protection of
certain health information. HHS issued the Privacy Rule to implement the Health
Insurance Portability and Accountability Act of 1996 (HIPAA, P.L. 104-191). The
Privacy Rule regulates the use and disclosure of protected health information (PHI)
(which is generally defined as individually identifiable health information) by
covered entities (which are health plans, health care clearinghouses, and health care
providers who transmit any health information in electronic form in connection with
a transaction for which HHS has developed standards, e.g., Medicare claims).144
Examples of PHI include name, address, birth date, social security number,
diagnosis, and more.145 The Privacy Rule requires IRBs or privacy boards146 to
review requests for information and carry out its provisions. The Privacy Rule may
thus create some new responsibilities for some IRBs.
The Privacy Rule prohibits a covered entity from disclosing PHI for research
without the patient’s authorization (45 CFR 164.508(a)(1)),147 whereas the Common
Rule requires informed consent in order to conduct research on a subject (45 CFR
46.116). The Privacy Rule specifically permits authorization to be combined with
informed consent (45 CFR 164.508(b)(3)(i)). In addition, in some circumstances —
including the conduct of research — the Privacy Rule’s requirements may be
45 CFR 160.103. See also, HHS, OCR, “Summary of the HIPAA Privacy Rule,” May
2003, at [http://hhs.gov/ocr/privacysummary.rtf], visited Apr. 11, 2005.
Protected health information means individually identifiable health information, except
as otherwise provided in 45 CFR 160.103. See also HHS, Office for Civil Rights (OCR),
“Privacy Brief: Summary of the HIPPA Privacy Rule,” at [http://www.hhs.gov/ocr/
privacysummary.pdf], visited Apr. 11, 2005.
A privacy board is defined in 45 CFR 164.512(i)(1)(i)(B).
The Privacy Rule specifically permits authorization to be combined with informed
consent 45 CFR 164.508(b)(3)(I). In addition, in many circumstances, including the conduct
of research, the Privacy Rule’s requirements may be satisfied by either informed consent or
authorization. See, e.g., 45 CFR 164.532(a).
satisfied by either informed consent or authorization(see, e.g., 45 CFR 164.532(a)).
Authorization’s requirements are tailored to its purpose of giving permission to
disclose a person’s personal health information.148 Those of informed consent are
tailored to its purpose of giving permission to conduct research on the person him or
The Privacy Rule and the Common Rule may jointly govern some research, but
apply differently from one another in the following key areas:150
Scope. The Privacy Rule has a different scope than the Common Rule. While
the Common Rule attaches when there is a federal funding source (45 CFR
46.101), the Privacy Rule applies regardless of funding source, but restricts only
the actions of covered entities: health plans, health care clearinghouses, and
health care providers who transmit any health information in electronic form in
connection with a transaction for which HHS has developed standards (e.g.,
Medicare claims).151 The Privacy Rule restricts covered entities’ disclosure of
PHI, whether in an electronic or other form.
Background Research. The Privacy Rule requires no oversight in one
circumstance where the Common Rule necessitates prior IRB review. The
Privacy Rule permits a covered entity to use and disclose PHI for research
purposes, without an individual’s authorization, provided the covered entity
obtains representations from the researcher that the use or disclosure of the PHI
is solely to prepare a research protocol or for similar purpose preparatory to
research, that the researcher will not remove any PHI from the covered entity,
and that PHI for which access is sought is necessary for the research.152 The
Common Rule would classify the same background investigation into patient
health records as “human subjects research” and would thus require prior IRB
approval (45 CFR 46.102(d), (f)(2)).
Databases, Repositories, and Unspecified Future Research. The Privacy Rule
requires a patient’s authorization for the release of PHI, in some cases in which
For a complete list of the requirements for authorization, see 45 CFR 46.508(c).
For a complete list of the elements of informed consent, see 45 CFR 46.116.
For an overview of many unresolved issues that exist between the Privacy Rule and the
Common Rule, see Mark Rothstein, “Research Privacy Under HIPAA and the Common
Rule,”Journal of Law, Medicine, and Ethics, vol.33, no. 1 (Spr. 2005), pg. 154.
45 CFR 160.103. See also HHS, OCR, “Summary of the HIPAA Privacy Rule,” May
2003, at [http://hhs.gov/ocr/privacysummary.rtf], visited Apr. 11, 2005.
45 CFR 164.512(i). According to the same provision, a covered entity may also disclose
PHI without an individual’s authorization, provided the covered entity obtains either: (1)
documentation of a waiver approval by an IRB or privacy board; or (2) in certain
circumstances, representations from the researcher that the use or disclosure sought is solely
for research on decedents’ PHI. Section 164.512(j) makes allowances for disclosure without
authorization to avert a serious threat to health or safety. Section 164.514(e) provides that
a covered entity also may use or disclose a limited data set of PHI (largely anonymized data)
for research purposes without an individual’s authorization.
the Common Rule does not require informed consent. To obtain PHI from a
database or repository, or to reuse it in the future, the Privacy Rule requires the
researcher to obtain the specific authorization of each individual whose health
information was procured, specifically prohibiting the combination of
authorizations for various research projects (compound authorization) (45 CFR
164.508(b)(3)).153 The Common Rule contains no equivalent prohibition. Some
who conduct registry or database research have questioned the necessity of
obtaining specific authorization for each disclosure as the Privacy Rule requires,
claiming that the requirement is burdensome, and that other adequate privacy
safeguards could be implemented.154
Post-Mortem Research. The Privacy Rule has a requirement regarding research
on cadavers that the Common Rule does not. The Privacy Rule’s definition of
“individual” is not limited to living persons.155 Therefore the Privacy Rule
would require researchers to obtain authorization from a legal representative of
the deceased before conducting research on deceased persons. The Common
Rule limits its definition of “human subjects” to the living, and therefore does
not apply to post-mortem research (45 CFR 46.102(f)).
IRB Role. While privacy and confidentiality issues are involved in all forms of
research involving human participants, the focus of IRB review under the
Common Rule is to protect the safety of individuals enrolled in clinical
research.156 However, in the rapidly expanding field of health services research
(HSR),157 which typically involves the secondary analysis of large databases of
medical records previously collected for other purposes, the principal risk to
participants is not physical harm, but a loss of privacy. The Common Rule
specifies that IRBs may only approve research that is judged to have adequate
provisions to protect the privacy of subjects and to maintain the confidentiality
of data, (45 CFR 46.111(a)(7)), and requires that informed consent include a
statement describing the extent, if any, to which confidentiality of records
identifying the subject will be maintained (45 CFR 46.113(a)(5)). Even so, it
does not provide any additional requirements, stipulate acceptable protection
provisions, or define terms. The Privacy Rule may thus significantly expand the
function of IRBs, by requiring them to weigh the potential threats to privacy
There are a few exceptions to this requirement, specified in 45 CFR 164.532.
See, e.g., Julie Ingelfinger and Jeffrey Drazen, “R egistry Research and Medical Privacy,”
New England Journal of Medecine., vol. 350, no. 14 (Apr. 1, 2004), p. 1452.
45 CFR 164.502(f): A covered entity must comply with the requirements of this Subpart
with respect to the protected health information of a deceased individual; 45 CFR 160.103:
Individual means the person who is the subject of PHI.
The emphasis of subject’s emphasis is reflected throughout the Common Rule, and
prominently in its title: Federal Policy for the Protection of Human Subjects.
Health services research is the study of the effects of using different modes of
organization, delivery, and financing for health care services. Its focus is on the
effectiveness of health care interventions in a real-world setting, whereas clinical research
concentrates on the efficacy of interventions in the controlled setting of a clinical trial.
before granting a researcher access to participants’ medical information without
Groups representing the biomedical research community have expressed
concern over the Privacy Rule’s impact on research previously only governed by the
Common Rule. A survey conducted by the Association of American Medical
Colleges found that the Privacy Rule had the following effects on research:159
Research subjects were confused and distracted by having to both
consent to participate in research (as per the Common Rule) and
authorize use of their PHI (as per the Privacy Rule).
Collaborations became more difficult because the Privacy Rule
requires authorization for PHI to be shared among institutions, and
the Common Rule does not.
The quality of research was diminished, and research costs were
raised because of the authorization requirements, which require a
subject to assent before each separate disclosure of their PHI. The
Common Rule has been interpreted to allow a one-time consent for
The positive effects of the Privacy Rule on individual privacy are more difficult
to document. However, it does make explicit requirements that must be met before
personally identifiable health information can be disclosed.
The interaction of the Privacy Rule and the Common Rule was one topic
addressed by the SACHRP. At a meeting in March 2004, SACHRP created a
drafting committee to develop recommendations concerning the revision of the
Privacy Rule to achieve greater harmonization with the Common Rule, ensure
protection of privacy rights, and reduce the regulatory burden.160
Food and Drug Administration
The FDA is the HHS agency responsible for protecting the public health by
assuring the safety, efficacy, and security of human and veterinary drugs, biological
products, medical devices, and for advancing the public health by helping to speed
innovations that make medicines and foods more effective, safer, and more
affordable. FDA also helps the public obtain the accurate, science-based information
The preamble to the Privacy Rule notes that waivers will rarely apply to clinical trials,
because the researchers are likely to have contact with the research subjects and be able to
seek authorization to use their medical information. Waivers are more likely to be sought
in HSR. Investigators conducting HSR may not have the ability to contact the original
subjects, and even if locating them is theoretically possible, the number of individuals may
be far too large to make contacting them practicable.
Susan H. Ehringaus, “AAMC Project to Document the Effects of HIPAA on Research,”
presentation to HHS SACHRP, Alexandria, VA, March 30, 2003, at [http://www.hhs.gov/
ohrp/sachrp/mtgings/mtg03-04/hipaaaamc_files/frame.htm], visited Apr. 11, 2005.
HHS, SACHRP, public meeting, Alexandria, VA, March 2004, at [http://www.hhs.gov/
ohrp/sachrp/mtgings/mtg03-04/mtg03-04.htm], visited Apr. 11, 2005.
they need to use medicines and foods to improve their health.161 In keeping with its
mission, the FDA regulates clinical research on human subjects that generates data
to support a company’s application for marketing (21 CFR Parts 50 and 56).
FDA regulations overlap with the Common Rule and 45 CFR 46 in instances
in which federally funded research is used to generate data for marketing
applications. As early as 1981, the FDA indicated that its regulations governing
human research subject protections and those governing IRB organization and
function were drafted to be as consistent as possible with the Common Rule. (46
Federal Register 8942 and 46 Federal Register 8942) However, differences between
FDA regulations and the Common Rule and 45 CFR 46 do exist, as do differences
in the agencies’ statutory authority and functions.
Harmonization of the regulations has been a topic of much discussion, the focus
of SACHRP recommendations to the HHS Secretary,162 and the target of some
proposed legislation. The following are some key differences between FDA
regulations and the HHS Regulations, which might be affected by harmonization:
(1) Scope. Where the Common Rule covers most basic and clinical research
conducted using federal funds (including social or behavioral research),163 FDA
regulations focus only on clinical investigations which support marketing
applications from companies seeking to place biomedical products in interstate
commerce. (21 CFR 50.1(a)) The difference in scope of the two sets of
regulations is relevant to harmonization efforts for two reasons. First, both sets
of regulations may apply to some research, which may create difficulty for
researchers when their requirements are dissimilar. Second, there are reports of
research not covered by either set of regulations, and therefore without any of
the federal human subjects protections that they provide.
(2) Definitions. The Common Rule specifies that a human subject must be living
(45 CFR 46.102(f)), FDA does not.164 Only FDA has distinct definitions for
investigator and sponsor(21 CFR 50.3(d), (e), and (f)). (By contrast, the
Common Rule defines institution, and research subject to regulation (45 CFR
46.102(b) and (e)).)
FDA, “FDA’s Mission Statement,” at [http://www.fda.gov/opacom/morechoices/
mission.html], visited Apr. 11, 2005.
Letter from Ernest D. Prentice to Secretary Thompson, Sep. 1, 2004, at
[http://www.hhs.gov/ohrp/sachrp/hipaalettertosecy090104.html], visited July 11, 2005.
45 CFR 46.101. This provision lists a detailed description of who is covered by the
regulation, including some exceptions for anonymized data for educational testing.
“Human subject means an individual who is or becomes a participant in research, either
as a recipient of the test article or as a control. A subject may be either a healthy human or
a patient”(21 CFR 50.3(g)).
(3) Emergency Use. FDA allows investigators to use test articles (unapproved
medicines or devices)165 without the consent of human subjects in certain
emergency situations. Highlights of the seven conditions that must be met
include the following: the human subjects are in a life-threatening situation,
available treatments are unproven or unsatisfactory, and the collection of valid
scientific evidence, which may include evidence obtained through randomized
placebo-controlled investigations, is necessary to determine the safety and
effectiveness of particular interventions.166 While HHS has adopted its own
emergency use provision,167 the Common Rule as adopted by signatory federal
agencies and departments has no emergency use provision.
(4) Financial Conflicts of Interest. Both the Common Rule and FDA regulations
state that no member of IRB may participate in IRB’s initial or continuing
review in which the member has a conflicting interest (45 CFR 46.107(e)
(HHS); 21 CFR 56.107(e) (FDA)). However, only FDA requires certification
and disclosure of financial conflicts for investigators (21 CFR 54).
(5) International Research. Both the Common Rule and FDA regulations apply
to research conducted outside of the United States, provided that it falls within
their respective scopes. However, the Common Rule allows a department or
agency head to approve the substitution of foreign procedures in lieu of its own
if he or she determines that the procedures prescribed by the institution afford
protections that are at least equivalent to those provided in the Common Rule
(45 CFR 46 46.101(h)). FDA regulations to not allow department or agency
heads to waive FDA regulations’ requirements to conduct a foreign clinical trial
under an IND. However, the FDA regulations do contain provisions for
incorporating the results of a foreign clinical trial not conducted under an IND
into an application for marketing, provided that the study was well designed,
well conducted, performed by qualified investigators, and conducted in
accordance with ethical principles acceptable to the world community (e.g., the
Declaration of Helsinki) (21 CFR 312.120).
(6) Parental Consent. Both 45 CFR 46 (Subpart D — which is not a part of the
Common Rule) and FDA generally require the permission of a parent or
guardian and the assent of the child for a child to participate in a clinical trial
(45 CFR 46.408(b) (HHS); 21 CFR 50.55(e) (FDA)). However unlike FDA,
Subpart D further stipulates that the IRB may waive the parental consent
requirement if it is not reasonable to protect the subjects (e.g., abused or
neglected children). In that case, an alternative appropriate mechanism for
protecting the children can be substituted (45 CFR 46.408(c)).
“Test article means any drug (including a biological product for human use), medical
device for human use, human food additive, color additive, electronic product, or any other
article subject to regulation under the act or under sections 351 and 354-360F of the Public
Health Service Act (42 U.S.C. 262 and 263b-263n)” (21 CFR 50.3(j)).
The lengthy set of FDA’s rules regulating Emergency Use appear at 21 CFR 50.24.
45 CFR 46.101(i) allows a waiver of the informed consent requirements of 45 CFR 46
in certain narrowly defined types of research in emergency situations (61 Federal Register
51531[Oct. 2, 1996]).
Proposed Legislation Related to Harmonization. H.R. 3594 (108th
Congress) would have required harmonization of 45 CFR 46 (including the Common
Rule) and FDA regulations within three years, followed by formal rule-making. In
preparation, the bill would have required that the HHS Secretary review the Common
Rule and 21 CFR 50 and 56 not later than 18 months after the enactment of the act.
The review would have determined to what extent the differences in approach
between the two sets of regulations could have been harmonized, with the goal of
having only such differences remain as reflected the legal or factual variations in the
human subject research. The areas of difference reviewed would have included (but
would not have been limited to) differences regarding the existence of a significant
financial interest; provisions for research relating to emergency interventions; the
definition of institution; and requirements for attestations by clinical investigators
regarding the protection of human subjects.
H.R. 3594 (108th Congress) would have also required the Secretary to publish
in the Federal Register, not later than 18 months after the enactment of the act, a
determination regarding whether research with data that do not involve any
interaction or intervention with a living human should be considered human subject
research. S. 3060 (107th Congress) did not address harmonization between agencies
per se, but would have applied all of the 45 CFR 46 Subparts to as broad a range of
research as possible, regardless of where it was conducted, by what agency it was
funded, or whether it was conducted for an application for FDA.
Appendix B. History and Requirements
of the Common Rule
International Codes and Declarations
The first sets of rules governing biomedical research arose from international
traditions and agreements. The emergence of three notable sets, the Hippocratic
Oath, the Nuremberg Code, and the Declaration of Helsinki, document the shift from
a paternalistic research model, assuming that the physician knew best, to an
autonomous model, mandating full understanding by and consent of subjects. Not
until 1962 did the United States created its own set of regulations.
Hippocratic Oath: Doctor Knows Best. Prior to the 1940s, biomedical
research was subsumed by the practice of medicine. Research was conducted
primarily by physicians in clinical settings, with little or no external review,
oversight, or informed consent. No research-specific ethical or legal framework
controlled investigations was in place.
Medical practice and research were governed by the Hippocratic Oath, the first
set of Western writings about medical practice. The Oath was rooted in the ethical
principles of non-maleficence (directing physicians not to harm patients) and
beneficence (directing physicians to benefit patients), with little concern for
autonomy (directing physicians to respect the informed decisions of patients). One
version of the Oath advised the wisdom of “concealing most things from the patient
while you are attending to him, . . . turning his attention away from what is being
done to him, . . . [and] revealing nothing of the patient’s future or present
The Hippocratic Oath placed decisions about medical care and research in the
hands of physicians who had more scientific and medical knowledge than their
patients. Decision-making by lay-person was perceived to be a burden physicians
should alleviate rather than a right they should respect.
Nuremberg Code: Subject’s Choice. In the 1940s, the wake of the
Holocaust changed the research paradigm, when Nazi doctors with recognized
medical credentials performed “medical experiments without the subjects’ consent,
upon civilians. . . [resulting in] murders, brutalities, cruelties, tortures, atrocities, and
other inhuman acts.”169 As a part of the judgement against the physicians, the first
ethical research principles were enacted in the Nuremberg Code. The Code was not
specifically adopted into United States law, but later became a basis for a Department
of Defense policy and the regulations that govern the protection of human subjects
in most federally funded research in the United States: 45 CFR 46.
Ruth Faden and Tom Beauchamp, A History of Informed Consent (Oxford: Oxford
University Press, 1986), p. 2.
Trials of War Criminals before the Nuremberg Military Tribunals under Control Council
Law no. 10. Nuremberg, October 1946-April 1949, (Washington: GPO, 1949-1953), p. 11.
Topping the list of principles listed in the Nuremberg Code was a requirement
that a researcher obtain voluntary consent of the human subject.170 Medical
researchers were to no longer make decisions on their subjects’ behalf, but instead
were to effectively convey information about the proposed research to competent
potential subjects, and allow them to decide whether to participate. This was a
dramatic shift in practice.
Subsequent provisions in the Nuremberg Code instructed researchers to ensure
that the potential benefits outweighed the risks of research, and to minimize those
risks. Researchers were also prohibited from causing permanent harm or death to
The Nuremberg Code did not resolve all possible issues. It lacked detail, failing
both to describe how consent was to be obtained, and was not capable of handling
complex issues arising out of advances in social science and biomedical research.171
The Code was also not immediately accepted by some researchers in the United
States, who conducted subsequent studies on populations lacking the capacity to
consent, such as the mentally retarded (lacking the element of comprehension) and
prisoners (lacking the element of free will).172
Declaration of Helsinki: Physicians Sign On. In 1964, the World
Medical Association created its own code to help maintain public trust in biomedical
research: the Declaration of Helsinki.173 It was the first code prescribed by an
internationally recognized body of medical professionals that embraced the concept
of informed consent. However, it allowed physicians considerable latitude when
conducting research with the hope of saving life, re-establishing health, or alleviating
suffering.174 Physicians conducting this therapeutic research were instructed to obtain
informed consent “consistent with patient psychology,”175 implying that consent was
not needed if it were inconsistent with patient psychology, a term the Declaration did
not define. This therapeutic loophole was closed in later amended versions of the
Trials of War Criminals Before the Nuremberg Military Tribunals, pp. 181-182.
Faden and Beauchamp, A History and Theory of Informed Consent p. 156.
David J. Rothman, Strangers at the Bedside (New York: Basic Books, 1991), p. 62.
Faden and Beauchamp, A History and Theory of Informed Consent, p. 156.
“Human Experimentation: Code of Ethics of the World Medical Association,” British
Medical Journal, vol. 2, no. 177 (1964).
Ibid. A situation in which consent might be inconsistent with patient psychology might
be, for example, one in which informed consent would require the disclosure of a
previously-unrevealed illness that a treating physician wished to conceal, so as not to
impede the healing process by distressing the patient.
World Medical Association Declaration of Helsinki, Adopted by the 18th WMA General
Assembly, Helsinki, Finland, June 1964, and amended by the 29th WMA General
Assembly, Tokyo, Japan, Oct. 1975, 35th WMA General Assembly, Venice, Italy, Oct.
1983, 41st WMA General Assembly, Hong Kong, Sept. 1989, 48th WMA General
United States Regulations Before the Common Rule
Congress has been involved in the examination of biomedical ethics issues since
the1960s, and played a vigorous role in the early history of federal involvement in
protecting human research subjects. Much of this was spurred by public disclosures
of events that involved morally unacceptable and often dangerous investigations on
human subjects. The HHS (formerly DHEW), was the first federally funded agency
to openly develop formal policies for the protection of human subjects.177 Most of
the details of the initial policies in this area were developed by two HHS agencies,
the NIH, and the FDA.178
NIH Clinical Center Policy of 1953. In 1953, the NIH opened its Clinical
Center to conduct biomedical research. That same year, in the shadow of the Nazi
medical experiments, the NIH Director adopted an intramural policy requiring
informed consent and “group consideration” of clinical research procedures that
“deviated from acceptable medical practice or involved unusual hazard.”179 The
policy introduced the notion that some, though not all research protocols should be
reviewed by someone other than the principal investigator in the study. However, it
only applied to some NIH research protocols, and it had no application to research
conducted outside of NIH. Officials anticipated widespread adoption and use of this
policy by other federal agencies, though it never occurred.180
Drug Amendments of 1962. Two years prior to the enactment of the
Declaration of Helsinki, the births of deformed infants whose mothers had taken a
sedative called thalidomide, focused public attention on pending United States
Assembly, Somerset West, Republic of South Africa, Oct. 1996, and the 52nd WMA
General Assembly, Edinburgh, Scotland, Oct. 2000.
In 1953, Secretary of Defense Charles Wilson issued a top secret memorandum
establishing policy for research related to atomic, biological, and chemical warfare. The
policy incorporated the principles of the Nuremberg Code and two additional protections
— a prohibition on research involving prisoners of war and a requirement that the Secretary
of the appropriate military service approve research studies. National Bioethics Advisory
Commission, Ethical and Policy Issues in Research Involving Human Participants, Aug.
FDA did not become part of HHS until 1968.
NIH, Group Consideration of Clinical Research Procedures Deviating from Accepted
Medical Practice of Involving Unusual Hazard, (Memorandum, approved by the Director,
NIH, 1953), cited in, John C. Fletcher, “Location of the Office for Protection from Research
Risks Within the National Institutes of Health: Problems of Status and Independent
Authority,” in NBAC, Ethical and Policy Issues in Research Involving Human Participants,
Volume II, Commissioned Papers and Staff Analysis (Bethesda: NBAC), p.B-10.
Faden and Beauchamp, A History and Theory of Informed Consent, pp. 201-202.
legislation.181 Thalidomide was widely used in Europe. Although not approved by
the FDA,182 the drug maker had supplied thalidomide to thousands of physicians in
the United States to conduct clinical investigations to establish the drug’s safety.
Many of the women who received thalidomide in this way were not informed that
they were participating in a study.183 The drug caused some babies to be born with
a rare defect known as Phocomelia Syndrome, which is characterized by missing or
deformed arms and/or legs. Other symptoms may include growth and mental
deficiencies, and defects in the eyes, ears, and nose.184
Impelled in part by the phocomelia-thalidomide connection, Congress
unanimously enacted the United States’ first law governing research on human
beings: the Drug Amendments of 1962 (P.L. 87-781),185 which amended the Federal
Food, Drug, and Cosmetic Act of 1938. The Amendments instructed the then
DHEW Secretary to issue regulations requiring FDA to review new drugs for efficacy
as well as safety, and to obtain subjects’ informed consent for research. A proposal
from Senator Jacob Javits would have required informed consent prior to the
administration of any investigational drug, however other Senators voiced concerns
that such a requirement would adversely affect physician-patient relationships.186 As
a result, FDA’s regulations allowed researchers to forego the consent process if they
deemed it not feasible or in their professional judgement, contrary to the best
interests of such human beings (Food, Drug, and Cosmetic Act, § 505, 520).
Following the publication of FDA regulations, concerns emerged that their
consent provisions were poorly developed and led to ambiguities. In response, FDA
published, Consent for Use of Investigational New Drugs on Humans: Statement of
Policy in August 1966.187 The new provisions were closely modeled after the
Nuremberg Code and the Declaration of Helsinki. The regulations applied only to
experimental drugs, devices, and biologics. They required researchers to advise
subjects of any existing alternative therapies, to tell subjects that they could be used
as study controls, and to obtain subjects’ written informed consent.
Events Leading Up to the Common Rule
By mid-1960, NIH officials began to have some concerns about its regulation
of human subjects research. They questioned the agency’s tradition of relying
exclusively on the moral character of investigators to safeguard human subjects, and
Food and Drug Administration, “The Story of the Laws Behind the Labels, Part 3, 1962
Drug Amendments,”FDA Consumer, June 1981, at [http://vm.cfsan.fda.gov/~lrd/
histor1b.html], visited Apr. 11, 2005.
At the time, FDA’s prior approval of investigational studies was not required.
Congressional Record, Aug. 23, 1962, pp. 17395-17403.
For further information about Phocomelia Syndrome, see
[http://my.webmd.com/hw/health_guide_atoz/nord780.asp], visited Apr. 11, 2005.
Section 505(i) of the Food, Drug, and Cosmetic Act of 1962.
Rothman, Strangers at the Bedside, pp. 63-67.
Faden and Beauchamp, A History and Theory of Informed Consent, p. 204.
its lack of systems to monitor the conduct of its investigators. Since the end of
World War II, NIH’s budget had grown from $2.8 million in 1945 to $773.1 million
in 1965 (a 276-fold increase).188 In 1965, NIH awarded 11,000 research grants, about
one-third of which involved human experimentation.189
Reports of Unethical Practices. In January 1962, the Law-Medicine
Research Institute in Boston (MA) published results of a DHEW-funded survey of
research practices in medical departments. Of the respondents,190 only a few had
procedural guidelines governing human subjects research, and about a third had
special consent forms for research projects. In addition, most institution officials
considered even self-regulation by committees unacceptable, preferring to leave these
procedures exclusively to investigators. The report concluded that internal
institutional regulation of research was erratic.191
In November 1964, NIH Director Shannon received a report from the agency’s
research resource division.192 It warned of “possible repercussions of untoward
events which are increasingly likely to occur” in “unfavorable” circumstances,
including events that could “rudely shake” the NIH. The report cited the absence of
an applicable code of conduct for research and an uncertain legal context as specific
concerns, among others.
In 1966, Henry Beecher published 22 detailed cases of research which contained
serious or potentially serious ethical violations. Only two studies mentioned
obtaining informed consent. Others allowed subjects to suffer preventable illness and
even death, replacing known therapies with placebos. In one study, control subjects
with typhoid fever did not receive chloramphenicol (a recognized treatment),
resulting in the preventable deaths of an estimated 23 patients.193
1966 Surgeon General’s Policy. On February 8, 1966, the United States
Surgeon General responded to the criticism by publishing a new policy: “Clinical
Investigations Using Human Subjects.” The policy required all PHS-funded
institutions to provide prior review by a committee for proposed investigations with
human subjects. The committees were charged with assessing the rights and welfare
NIH, Office of the Director, NIH Almanac 2002,NIH Publication No. 02-5, December
2002, at [http://www.nih.gov/about/almanac/appropriations/part2.htm], visited Apr. 11,
Rothman, Strangers at the Bedside, p. 54.
Eighty-six (86) surveys were sent out, and fifty-two (52) institutions responded.
“A Study of the Legal, Ethical, and Administrative Aspects of Clinical Research
Involving Human Subjects: Final Report of Administrative Practices in Clinical Research,”
[NIH] Research Grant No. 7039 Law-Medicine Research Institute, Boston University, 1963
(ACHRE No. BU-053194-A).
Robert B. Livingston, Associate Chief for Program Development, Memorandum to the
Director, NIH, Progress Report on Survey of Moral and Ethical Aspects of Clinical
Investigation, Nov. 4 1964 (ACHRE No. HHS-090795-A).
Henry K. Beecher, “Ethics and Clinical Research,” New England Journal of Medicine,
vol. 274, no. 24 (Jun 16, 1966), pp. 1354-1360.
of the research subject, the appropriateness of informed consent method, and the
balance of risks and benefits. (21 CFR 310.102(f)) The policy, while addressing the
issue of self-regulation, did not adequately define key terms such as “rights and
welfare of potential subjects,” “informed consent,” and risks and potential benefits.”
According to one account, the lack of definitions confused committees and led to
arbitrary application of the policy.194
1971 DHEW Guide. In 1971, DHEW expanded the Surgeon General’s policy
and defined many of the missing terms in its “Institutional Guide to DHEW Policy
on Protection of Human Subjects.” The Guide offered clarifications, such as a listing
of the elements of informed consent, and added a requirement that ongoing research
projects be continually reviewed.195 However, issues remained regarding the
composition of the institutional review committees, compensation for injury during
an investigation, ensuring an equitable research subject selection process, and the
achievement of adequate informed consent.196
The Tuskegee Study. In July 1972, Jean Heller, a reporter with the
Associated Press, released a story about a PHS-funded study that shocked the public
and the research community: the Tuskeegee syphilis study. As documented in the
book Bad Blood,197 to investigate the continuing effects of syphilis, PHS-funded
researchers withheld treatment from hundreds of African-American men in
Tuskeegee, Alabama for 40 years (19 years past the discovery of penicillin, which
can cure the disease). The untreated disease left many men blinded, insane, and even
A DHEW ad hoc advisory committee investigation of Tuskeegee found that the
study was ethically unjustified, and that penicillin therapy should have been made
available to all study subjects when it was made available for treatment of syphilis.198
The panel also found that neither DHEW, nor any other government agency had
policy in place to adequately review experimental procedures, or to adequately obtain
informed consent from research subjects. It recommended that Congress create a
permanent body with authority, at a minimum, to regulate all federally supported and
conducted research involving human subjects.
DHEW and Congress Take Action. On May 30, 1974, DHEW replaced its
1966 policy by publishing more robust and comprehensive regulations governing the
protection of human subjects. (45 CFR 46) One month later, Congress passed the
National Research Act (P.L. 93-348), which created the National Commission for the
Faden and Beauchamp, A History and Theory of Informed Consent, p. 211
President’s Commission for the Study of Ethical Problems in Medicine and Biomedical
and Behavioral Research, Protecting Human Subjects, GPO 040-000-00452-1, Dec. 1981,
Faden and Beauchamp, A History and Theory of Informed Consent, p. 213.
James H. Jones, Bad Blood (New York, Free Press, 1981 and 1993).
J. S. Reiser, et al., Ethics in Medicine, from Final Report of the Tuskegee Syphilis Study
Ad Hoc Advisory Panel, [reprinted from the Final Report; Washington, D.C., United States
PHS, pp. 5-15] (Cambridge, MA: MIT Press, 1977).
Protection of Human Subjects of Biomedical and Behavioral Research (the National
Commission) and directed it to make recommendations to the DHEW Secretary
about the ethical principles that should underlie human subjects research. The act
also required grantees and contractees under the Public Health Service Act to
establish IRBs to review research involving human subjects.
45 CFR 46, Subpart A: The Basis of the Common Rule
Subpart A of the 1974 regulations — basic HHS Policy for Protection of Human
Research Subjects — was adopted by a many, but not all, federal agencies on June
18, 1991. It became known as the Common Rule (56 Federal Register 28003)
The final form of the Common Rule and its adoption by agencies other than
HHS were due in large part to the recommendations of two Commissions. The first,
the National Commission for the Protection of Human Subjects of Biomedical and
Behavioral Research (The National Commission), was created on July 12, 1974 with
the passage of the National Research Act (P.L. 93-348). The act also required
grantees and contractees under the Public Health Service Act to establish IRBs to
review research involving human subjects. The National Commission was directed
to consider, among other things, the ethical principles that should underlie human
subjects research. Its work culminated in the issuance of the Belmont Report,199
which sets forth the following three principles:
Principal of Respect for Persons: Consideration must be given to
individuals’ autonomy. (This principle underlies the requirement of
obtaining informed consent.)
Principal of Beneficence: Research must be shown to be beneficial
and reflect the Hippocratic ideal of doing no harm.
Principle of Justice: The potential benefits of research must be
balanced against the risks to subjects.
In 1980, DHEW official became HHS, and in response to the Belmont Report, the
HHS and the FDA significantly revised their human subjects regulations in 1981 (45
CFR 46; 21 CFR 50).
The second commission responsible for the adoption of the Common Rule was
the President’s Commission for the Study of Ethical Problems in Medicine and
Biomedical and Behavioral Research (the President’s Commission). From 19821983, the President’s Commission analyzed the adequacy and uniformity of the rules
and procedures of some 23 Federal entities reporting that they conducted or
supported research with human subjects. In its final report, “Implementing Human
Research Regulations: The Adequacy and Uniformity of Federal Rules and of Their
National Commission for the Protection of Human Subjects of Biomedical and
Behavioral Research, Belmont Report, Apr. 18, 1979, (OS) 78-0013 and No. (OS) 78-0014,
Implementation,” it found that the DHEW 1974 policy was the benchmark of
“adequacy” for protecting human research subjects.200
Basic Requirements of the Common Rule. The Common Rule was
broader, and more comprehensive than the 1971 DHEW guide. It contained the
following basic requirements (for a comprehensive list, see 45 CFR 46, Subpart A):
Intramural and Extramural Application. The Common Rule applied
not only to research conducted outside of NIH as the 1966
regulations had, but also that conducted on NIH’s campus.
Institutional Assurances. Each institution that conducts research
involving human subjects must first submit written “assurance”
satisfactory to the department or agency head that it will comply
with the requirements in 45 CFR 46, including a statement of human
subjects protection principles (e.g., Nuremberg Code, Helsinki
Code). The institution also must certify that the research has been
reviewed and approved, and will be subject to continuing review by
an IRB provided for in the assurance.
Broader, Ongoing IRB Review.
Review of all protocols. The new policy required external review of
all human subjects research, not just those judged by the principal
investigator to present risk to human subjects.201 The IRBs, and not
investigators, would determine the extent of any risk involved and
check the informed consent protocols.
Conduct Ongoing Review. IRBs would be required to periodically
re-review ongoing research.
Meet Membership Requirements. The IRB must be composed of a
minimum of five qualified members of varied backgrounds.
Specified Informed Consent Requirements. The basic elements of
informed consent are as follows (additional elements of informed
consent for specific circumstances can be found in 45 CFR 46.116.):
A statement that the study involves research, an explanation of the
purposes of the research as well as the expected duration of the
subject’s participation, a description of the procedures that will be
followed, and identification of any experimental procedures;
A description of any reasonable foreseeable risks or discomforts to
the research subject;
A description of any benefits to the research subjects or to others
which may reasonably be expected from the research;
A disclosure of appropriate alternative procedures or courses of
treatment, if any, that might be advantageous to the research subject;
President’s Commission for the Study of Ethical Problems in Medicine and Biomedical
and Behavioral Research, The Adequacy and Uniformity of Federal Rules and of their
Implementation: Protecting Human Subjects (Washington, D.C.: GPO, 1983).
Certain low-risk types of research are exempt from the requirement of IRB review, for
example, research involving the use of educational tests (cognitive, diagnostic, aptitude
achievement) if information from such tests is recorded in such a way that subjects cannot
be identified. For other exemptions, see 45 CFR 46.101.
A statement describing the extent, if any, to which confidentiality of
records identifying the research subject will be maintained;
For research involving more than minimal risk, an explanation about
whether any medical treatments are available if injury occurs and, if
so, what they consist of, or whether further information may be
An explanation of whom to contact for answers to pertinent
questions about the research and research subjects’ rights, and whom
to contact in the event of a research-related injury to the subject; and
A statement that participation is voluntary, refusal to participate will
involve no penalty or loss of benefits to which the research subject
is otherwise entitled, and the subject may discontinue participation
at any time without penalty or loss of benefits to which the subject
is otherwise entitled.